Cancers

18 pages, 3086 KB

Open AccessArticle

Collagen Turnover Is Associated with Disease Severity, Bone Marrow Fibrosis, and the JAK2V617F Variant Allele Frequency in Myeloproliferative Neoplasms

by Caroline Norup Bistrup, Morten Kranker Larsen, Peter Junker, Vibe Skov, Lasse Kjær, Trine Alma Knudsen, Morten Karsdal, Nicholas Willumsen and Hans Carl Hasselbalch

Cancers 2026, 18(15), 2529; https://doi.org/10.3390/cancers18152529 - 6 Aug 2026

Viewed by 591

Abstract

Background and objectives: Myeloproliferative neoplasms (MPNs) are blood cancers characterized by elevated blood cell counts, bone marrow fibrosis (BMF), and chronic inflammation, which drives disease progression. BMF results from disrupted collagen turnover in the bone marrow extracellular matrix (ECM), making its reduction [...] Read more.

Background and objectives: Myeloproliferative neoplasms (MPNs) are blood cancers characterized by elevated blood cell counts, bone marrow fibrosis (BMF), and chronic inflammation, which drives disease progression. BMF results from disrupted collagen turnover in the bone marrow extracellular matrix (ECM), making its reduction or stabilization a key therapeutic goal. Non-invasive biomarkers reflecting collagen turnover could potentially improve early detection of BMF and monitor disease activity. Methods: We evaluated serum biomarkers of collagen turnover in 130 MPN patients (MPN subtypes: ET = 49, PV = 60, pre-PMF = 8, PMF = 13) included in the DALIAH trial (ClinicalTrials.gov identifier: #NCT01387763). Type I and type III collagen formation (PRO-C1 and PRO-C3) and MMP-degraded type I, III, and IV collagens (C1M, C3M, and C4M) were measured by ELISA in serum. Biomarker levels were compared to age- and sex-matched healthy individuals and were assessed according to disease subtypes, somatic driver mutations, JAK2V617F VAF, and fibrosis grade. Furthermore, we studied correlations between the biomarker levels and conventional hematological markers for disease activity, such as hemoglobin, white blood cell count (WBCs), platelet counts, and lactate dehydrogenase (LDH). Results: Baseline PRO-C3 (p = 0.0005) and C1M (p = 0.0102) were elevated in MPN patients compared to healthy individuals, whereas C3M was decreased (p < 0.0001). Patients with primary myelofibrosis (PMF) had higher levels of PRO-C3 compared to patients with ET (p = 0.0041) and PV (p = 0.0172), correlated with higher JAK2V617F VAF (≥50%) (p = 0.0069) and advanced fibrosis grade (p = 0.0002). In addition, PRO-C3 was positively correlated to LDH, which is a biomarker of disease activity in MPNs (r = 0.5754, p < 0.0001). Conclusions: Taken together, these findings emphasize the role of ECM remodeling in MPN pathophysiology and the potential of soluble ECM neoepitopes as biologically plausible disease markers. Full article

(This article belongs to the Section Molecular Cancer Biology)

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16 pages, 3527 KB

Open AccessArticle

Adult Sarcomas with NTRK Fusions: Clinicopathologic and Genomic Heterogeneity

by Michael Schwartz, Kieran Sweeney, Steven C. Smith, Kartik Angara, Celia Reynolds, Alberto S. Pappo, Andrew Elliott, Matthew J. Oberley, Mark G. Evans and Armita Bahrami

Cancers 2026, 18(15), 2528; https://doi.org/10.3390/cancers18152528 - 6 Aug 2026

Viewed by 488

Abstract

Background: NTRK gene fusions are established oncogenic drivers in a diverse spectrum of mesenchymal neoplasms. Although classically described in pediatric entities, NTRK-rearranged sarcomas also occur in adults, where their clinicopathologic features, genomic context, and response to TRK inhibition are less well characterized. Methods: [...] Read more.

Background: NTRK gene fusions are established oncogenic drivers in a diverse spectrum of mesenchymal neoplasms. Although classically described in pediatric entities, NTRK-rearranged sarcomas also occur in adults, where their clinicopathologic features, genomic context, and response to TRK inhibition are less well characterized. Methods: We retrospectively queried a national referral genomics database to identify sarcomas in patients >18 years harboring pathogenic NTRK1, NTRK2, or NTRK3 fusions. Gastrointestinal stromal tumors, duplicate specimens, and cases lacking digitized hematoxylin and eosin slides were excluded. Fusions were identified by whole-transcriptome sequencing, co-occurring genomic alterations by exome-based sequencing, and real-world survival and time on TRK inhibitor therapy were derived from linked insurance claims data; fusion-negative sarcomas and NTRK-rearranged non-sarcoma tumors from the same database served as comparison cohorts. Results: Among 13,040 profiled sarcomas, 19 adult tumors with pathogenic NTRK fusions were identified (median age, 43 years; range, 21–77), most of which were high grade (68%) and advanced stage (63% stage IV). Histology was heterogeneous, including spindle cell sarcoma (53%), pleomorphic sarcoma (21%), and tumors corresponding to defined entities such as NF1-associated malignant peripheral nerve sheath tumor and MDM2-amplified dedifferentiated liposarcoma (11% each). NTRK1 and NTRK3 fusions were equally frequent (9 cases each); fusion partners were diverse, with TPM3 (n = 5), EML4 (n = 2), and TFG (n = 2) recurrent and other partners non-recurrent. Additional genomic alterations were common and heterogeneous (72%), including high genome-wide loss of heterozygosity and infrequent but recurrent alterations involving the TERT promoter, NF1, and RB1. All evaluable tumors showed transcriptional activation of the NTRK fusion and increased MAPK pathway activity compared with fusion-negative sarcomas. Nine patients received TRK inhibitors; median time on larotrectinib was 12.5 months, similar to that observed in NTRK-rearranged non-sarcoma tumors, but treatment duration was variable. Conclusions: Adult sarcomas harboring NTRK fusions are rare, morphologically heterogeneous, and biologically diverse. NTRK fusion status alone may not fully capture oncogenic dependence and should be interpreted within the broader clinicopathologic and genomic context. Full article

(This article belongs to the Special Issue Soft Tissue Sarcomas—New Diagnostic and Therapeutic Perspectives Through Clinical Genomic Profiling)

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27 pages, 2457 KB

Open AccessArticle

Feasibility and Oncological Outcomes of Segmental Ureteral Resection Versus Radical Nephroureterectomy for High-Risk Ureteral Urothelial Carcinoma

by Yu-Hsiang Chang, Chao-Hsiang Chang, Chi-Ping Huang, Wen-Jeng Wu, Ching-Chia Li, Marcelo Chen, Wun-Rong Lin, Chih-Chin Yu, Vincent F. S. Tsai and Yao-Chou Tsai

Cancers 2026, 18(15), 2527; https://doi.org/10.3390/cancers18152527 - 6 Aug 2026

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Abstract

Background/Objectives: Radical nephroureterectomy (RNU) is the standard of care for high-risk upper tract urothelial carcinoma (UTUC) but causes permanent renal decline, often disqualifying patients from essential cisplatin-based adjuvant chemotherapy. Segmental ureteral resection (SUR) preserves renal function, but its safety in high-risk patients [...] Read more.

Background/Objectives: Radical nephroureterectomy (RNU) is the standard of care for high-risk upper tract urothelial carcinoma (UTUC) but causes permanent renal decline, often disqualifying patients from essential cisplatin-based adjuvant chemotherapy. Segmental ureteral resection (SUR) preserves renal function, but its safety in high-risk patients remains fiercely debated due to historical treatment selection biases and a lack of competing risk adjustments. We aimed to compare long-term oncological outcomes and postoperative renal function preservation between SUR and RNU for high-risk UTUC strictly localized to the ureter. Methods: Retrospective data from 859 patients (783 RNU, 76 SUR) with high-risk ureteral UTUC (high-grade or pathologic T2–T4) were analyzed from a 21-hospital nationwide database. Propensity score overlap weighting was implemented to achieve covariate balance. Overall survival (OS) was assessed via Cox proportional hazards regression, whereas cancer-specific survival (CSS), metastasis-free survival (MFS), and local recurrence-free survival (LRFS) were evaluated using multivariable Fine–Gray subdistribution hazard models to robustly account for the competing risk of non-cancer mortality. Results: Overlap weighting achieved excellent baseline comparability with an effective sample size of 429.5 patients per cohort. Weighted analyses demonstrated comparable long-term trajectories between SUR and RNU for OS (p = 0.62), CSS (hazard ratio [HR]: 0.94, p = 0.835), and MFS (HR: 0.88, p = 0.664). The Fine–Gray model confirmed that the surgical approach was not a significant independent predictor of local recurrence (HR: 0.74, p = 0.351). Crucially, the SUR group demonstrated a significantly lower renal function decline both at 1 month (−0.11 vs. −10.58 mL/min/1.73 m², p < 0.001) and through final clinical follow-up (−5.33 vs. −12.49 mL/min/1.73 m², p = 0.001). Conclusions: For meticulously selected patients with high-risk ureteral UTUC, SUR provides equivalent oncological control and survival outcomes to standard RNU. Crucially, this kidney-sparing approach significantly preserves postoperative renal function, safeguarding the physiological reserve required for patients to maintain eligibility for optimal subsequent systemic adjuvant therapies. Full article

(This article belongs to the Special Issue Advances in the Treatment of Urological Cancer)

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41 pages, 6383 KB

Open AccessReview

The Genetic Landscape of Colorectal Cancer: From Molecular Alterations to Therapeutic Decision Pathways

by Cristina Maria Macrea, Tiberia Ilias, Alexandra Costea, Paula Trif, Viorela-Romina Murvai and Ovidiu C. Fratila

Cancers 2026, 18(15), 2526; https://doi.org/10.3390/cancers18152526 - 6 Aug 2026

Cited by 1 | Viewed by 710

Abstract

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide despite substantial advances in screening, surgical techniques, systemic therapies, and multidisciplinary care. The increasing implementation of precision oncology has fundamentally transformed CRC management by enabling molecularly guided therapeutic [...] Read more.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide despite substantial advances in screening, surgical techniques, systemic therapies, and multidisciplinary care. The increasing implementation of precision oncology has fundamentally transformed CRC management by enabling molecularly guided therapeutic strategies based on tumor-specific genetic alterations. In recent years, the molecular landscape of CRC has expanded considerably beyond traditional histopathological classification, incorporating a growing number of clinically actionable biomarkers with prognostic, predictive, and therapeutic significance. This review provides a comprehensive and up-to-date overview of the genetic landscape of CRC, focusing on established biomarkers currently integrated into clinical practice, including microsatellite instability/mismatch repair deficiency (MSI/dMMR), KRAS, NRAS, BRAF, HER2, and NTRK alterations. In addition, emerging biomarkers such as tumor mutational burden (TMB), POLE/POLD1 mutations, circulating tumor DNA (ctDNA), DNA damage repair (DDR) alterations, transcriptomic signatures, and artificial intelligence-based molecular prediction models are critically discussed. Particular emphasis is placed on their biological significance, diagnostic methodologies, prognostic and predictive value, and potential role in treatment selection. A structured, database-informed narrative review identified 140 relevant publications, primarily published between January 2020 and June 2026, supplemented by earlier seminal studies and major clinical guidelines. Based on the available evidence, we propose a Clinical Actionability Framework for CRC, categorizing biomarkers into three hierarchical tiers according to their level of clinical validation and therapeutic relevance: established standard-of-care biomarkers, emerging clinical biomarkers, and future precision oncology biomarkers. Collectively, current evidence supports a progressive transition from single-gene testing toward integrated multi-omics precision medicine. Advances in comprehensive genomic profiling, liquid biopsy technologies, transcriptomics, radiogenomics, and artificial intelligence are expected to further refine patient stratification, optimize therapeutic decision-making, and facilitate the development of adaptive precision oncology models. Understanding the evolving genetic landscape of CRC is therefore essential for maximizing treatment efficacy and improving patient outcomes in the era of personalized cancer care. Full article

(This article belongs to the Section Cancer Therapy)

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31 pages, 1009 KB

Open AccessSystematic Review

Psychological Resources in Adults with Cancer: A Systematic Review of Quantitative Studies

by Morgiane Bridou and Léonore Robieux

Cancers 2026, 18(15), 2525; https://doi.org/10.3390/cancers18152525 - 6 Aug 2026

Viewed by 314

Abstract

Background/Objectives: Patients facing cancer’s challenges develop various coping strategies. This systematic review identifies the psychological resources that influence their mental health and quality of life. Methods: Following PRISMA guidelines, we searched Medline, PsycINFO, PubMed, Science Direct, Springerlink, and Wiley for empirical studies published [...] Read more.

Background/Objectives: Patients facing cancer’s challenges develop various coping strategies. This systematic review identifies the psychological resources that influence their mental health and quality of life. Methods: Following PRISMA guidelines, we searched Medline, PsycINFO, PubMed, Science Direct, Springerlink, and Wiley for empirical studies published between 2010 and 2025 for articles containing the term “cancer” and one or more terms relating to psychological resources. Including studies focused on peer-reviewed articles evaluating at least one psychological resource and one mental health outcome in adult cancer patients. A total of 95 studies (N = 21,683) were included after a formal screening process. Results: Risk of Bias in Non-randomized Studies—of Exposures (ROBINS-E) assessments of the risk of bias showed the overall quality of the included studies, with 89% of studies having a low or moderate risk of bias. The review identified 16 psychological resources. We described each resource’s impact based on the strength of current empirical evidence. Optimism, resilience, hope, and self-compassion emerged as the most prominent predictors of reduced psychological distress. By analyzing study designs, these resources were organized into a functional hierarchy reflecting their specific roles within the coping process. Conclusions: Based on this categorization, we propose a conceptual model illustrating the interplay between these resources. This framework suggests a theoretical basis for future empirical validation and provides directions for designing targeted psychological interventions. Full article

(This article belongs to the Special Issue Psychological Factors and Cancer Survivorship)

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11 pages, 2130 KB

Open AccessArticle

Retrieval-Augmented Generation-Enabled Multimodal Large Language Model for Histopathologic Grading of Cutaneous Squamous Cell Carcinoma and Melanocytic Nevi

by Joshua Mijares, Eric Gan, Neil K. Jairath, Judy Hamad, Ahmed Alomari, Vignesh Ramachandran and Syril Keena T. Que

Cancers 2026, 18(15), 2524; https://doi.org/10.3390/cancers18152524 - 6 Aug 2026

Viewed by 329

Abstract

Background: Histopathologic grading is an essential step in guiding treatment recommendations and follow-up for cutaneous lesions. However, inter-observer variability in determining differentiation of cutaneous squamous cell carcinoma (cSCC) and dysplasia of melanocytic nevi remain a challenge. Retrieval-augmented generation (RAG)-assisted artificial intelligence may [...] Read more.

Background: Histopathologic grading is an essential step in guiding treatment recommendations and follow-up for cutaneous lesions. However, inter-observer variability in determining differentiation of cutaneous squamous cell carcinoma (cSCC) and dysplasia of melanocytic nevi remain a challenge. Retrieval-augmented generation (RAG)-assisted artificial intelligence may offer educational and diagnostic support in this process. Methods: Two isolated RAG pathways using Claude 4.5 Opus, each grounded via ChromaDB vector retrieval of task-specific literature, graded 60 cSCC cases by differentiation and 67 melanocytic nevus cases by dysplasia. Each case was analyzed three times, with the majority result used as the final grade. Concordance with reference dermatopathologist grading was calculated with 95% Wilson score confidence intervals; inter-rater reliability was assessed using Cohen’s kappa. Results: For cSCC, the LLM achieved 90.0% concordance (95% CI, 79.9–95.3%) with excellent agreement (κ = 0.85, 95% CI, 0.74–0.96). For nevi, concordance was 44.8% (95% CI, 33.5–56.6%) with agreement not statistically distinguishable from chance (κ = 0.072, 95% CI, −0.10–0.24). Discordant nevus classifications skewed toward the moderately dysplastic category (65.7% of LLM classifications vs. 41.8% of reference classifications), and no severely dysplastic case was concordantly classified (0/6). Conclusions: Despite an identical RAG architecture, concordance with reference dermatopathologist grading was markedly task-dependent: high for cSCC differentiation, low for nevus dysplasia grading. This pattern parallels reported human inter-rater reliability for these tasks, suggesting that task-specific validation is needed before clinical or educational use. Full article

(This article belongs to the Special Issue Current Advances and Challenges in Skin Cancers)

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13 pages, 654 KB

Open AccessArticle

The Controlling Nutritional Status Score as a Predictive Factor for Lung Metastasis in Patients with Hepatocellular Carcinoma After Hepatectomy

by Jiro Kimura, Kosei Takagi, Tomokazu Fuji, Kazuya Yasui, Takeyoshi Nishiyama and Toshiyoshi Fujiwara

Cancers 2026, 18(15), 2523; https://doi.org/10.3390/cancers18152523 - 6 Aug 2026

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Abstract

Background/Objectives: Lung metastasis (LM) is the most common type of extrahepatic metastasis after hepatectomy for hepatocellular carcinoma. However, the predictive factors for LM after hepatectomy for hepatocellular carcinoma remain incompletely characterized. This study aimed to examine the predictive factors for LM after hepatectomy [...] Read more.

Background/Objectives: Lung metastasis (LM) is the most common type of extrahepatic metastasis after hepatectomy for hepatocellular carcinoma. However, the predictive factors for LM after hepatectomy for hepatocellular carcinoma remain incompletely characterized. This study aimed to examine the predictive factors for LM after hepatectomy for hepatocellular carcinoma and clarify the association between preoperative biomarkers and LM. Methods: We analyzed data of 644 consecutive patients with hepatocellular carcinoma who underwent primary hepatectomy between July 2003 and December 2023. Patients were divided into two groups: LM (+) and LM (−). Additionally, the association between perioperative factors and LM was investigated. Subsequently, a risk model was developed to predict LM. Results: Of the 644 patients, 43 (6.7%) experienced LM. Regarding biochemical scores, only the proportion of high Controlling Nutritional Status (CONUT) score (≥3) was significantly different (43.9% in the LM (−) group vs. 60.5% in the LM (+) group, p = 0.04). In multivariable analysis, a high CONUT score, tumor size, and microvascular invasion were identified as independent predictive factors for LM. The risk model exhibited accuracy with an area under the curve of 0.93, 0.85, and 0.83 in the 1-, 3-, and 5-year LM, respectively. Conclusions: The present study demonstrated an association between CONUT score and LM after primary hepatectomy for hepatocellular carcinoma and found that a high CONUT score is a complementary predictive factor for LM. Full article

(This article belongs to the Section Cancer Metastasis)

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13 pages, 1024 KB

Open AccessArticle

Reduced-Dose Regorafenib for Recurrent Glioblastoma: A Safety and Outcome Analysis

by Massimiliano Domenico Rizzaro, Claudia Fanizzi, Giorgio Fiore, Luigi Gianmaria Remore, Guido Del Vecchio, Elena Scagliotti, Giovanni Pratelli, Stefano Borsa, Stefania Elena Navone, Ilaria Bertorelli, Luca Enrico Sironi, Gabriella Roda, Giovanni Marfia, Manuela Caroli and Marco Locatelli

Cancers 2026, 18(15), 2522; https://doi.org/10.3390/cancers18152522 - 6 Aug 2026

Viewed by 338

Abstract

Background/Objectives: Recurrent glioblastoma has a poor prognosis and no universally accepted standard of care. Regorafenib has been investigated in this setting, but its use may be limited by treatment-related toxicity. This study evaluated the feasibility, safety, and clinical outcomes of reduced-dose regorafenib in [...] Read more.

Background/Objectives: Recurrent glioblastoma has a poor prognosis and no universally accepted standard of care. Regorafenib has been investigated in this setting, but its use may be limited by treatment-related toxicity. This study evaluated the feasibility, safety, and clinical outcomes of reduced-dose regorafenib in patients with recurrent IDH-wildtype glioblastoma. Methods: We retrospectively analyzed 21 patients with recurrent IDH-wildtype glioblastoma (WHO 2021) treated at a single center after progression according to the Stupp protocol. Regorafenib was started at 80 mg/day on the standard 3-weeks-on/1-week-off schedule. We assessed overall survival from diagnosis (OS1) and from first progression (OS2), progression-free survival from diagnosis (PFS1) and from first progression (PFS2), treatment exposure, dose modifications, and treatment-related adverse events (CTCAE v5.0). Results: Median PFS2 was 5 months (95% CI, 3–8), median OS2 was 6 months (95% CI, 5–10), and median OS1 was 21 months (95% CI, 15–27). No grade ≥ 3 adverse events occurred, and no patient discontinued treatment permanently because of toxicity. Conclusions: In this retrospective single-center cohort, reduced-dose regorafenib was feasible and well tolerated in selected patients. These descriptive, hypothesis-generating findings warrant prospective studies to define the role of individualized regorafenib dosing in recurrent glioblastoma. Full article

(This article belongs to the Special Issue Updates on Anti-Cancer Drug Research)

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13 pages, 2873 KB

Open AccessArticle

Burden of Mesothelioma in China, 1990–2023: Trends, Decomposition, and Projections Until 2045

by Kang Hu, Qichen Ye, Rongrong Zhao, Chao Ma, Xiao Zhang, Tianhao Xie, Chenye Shao, Cheng Ding, Jun Zhao and Hao Ding

Cancers 2026, 18(15), 2521; https://doi.org/10.3390/cancers18152521 - 6 Aug 2026

Viewed by 466

Abstract

Background: Mesothelioma is a rare but highly aggressive malignancy strongly associated with asbestos exposure. Owing to its long latency and poor prognosis, its burden requires systematic evaluation. Methods: Data on prevalence, incidence, deaths, disability-adjusted life years (DALYs), and age-standardized rates were [...] Read more.

Background: Mesothelioma is a rare but highly aggressive malignancy strongly associated with asbestos exposure. Owing to its long latency and poor prognosis, its burden requires systematic evaluation. Methods: Data on prevalence, incidence, deaths, disability-adjusted life years (DALYs), and age-standardized rates were extracted from the Global Burden of Disease Study 2023. The estimated annual percentage change, Joinpoint regression, Das Gupta decomposition, and Nordpred forecasting were used to assess temporal trends, identify turning points, quantify demographic and epidemiological contributions, and project future burden through 2045. Results: From 1990 to 2023, the absolute burden of mesothelioma in China increased substantially. Prevalent cases rose by 189%, incident cases by 150%, DALYs by 98%, and deaths by 142%. Males consistently showed a higher burden than females, and the burden was concentrated mainly among middle-aged and older adults. The age-standardized prevalence rate and age-standardized incidence rate increased, whereas the age-standardized DALY rate and age-standardized mortality rate remained stable or declined slightly. Decomposition analysis indicated that population growth and aging were the principal drivers of increased DALYs and deaths, while epidemiological change contributed negatively. Projections suggested that deaths may continue to increase through 2045, despite declining age-standardized fatal burden. Conclusions: This is the first update of the burden of mesothelioma in China over the past thirty-four years. The absolute burden of mesothelioma in China, as estimated by the GBD study, increased markedly, largely driven by demographic changes. Strengthening asbestos exposure surveillance, diagnostic standardization, and cancer registration systems would enable burden estimates to be derived from directly observed and certified data rather than relying primarily on model-based assumptions, while potentially identifying previously unrecognized sources of asbestos exposure. Full article

(This article belongs to the Special Issue Mesothelioma Today: Global Trends, Clinical Challenges, and Policy Responses)

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22 pages, 688 KB

Open AccessReview

Endoscopic Axillary Lymphadenectomy in Breast Cancer: Evolution, Current Evidence, and Future Perspectives

by Sandra López Gordo, Humberto M. Pontillo Zile, Lidia Blay Aulina, Marta Eguía Larrea, Anna Garcia-Monferrer, Raquel Arranz Jimenez, Isabel Prieto Nieto, Cristina Serra-Serra and Elisa York Pineda

Cancers 2026, 18(15), 2520; https://doi.org/10.3390/cancers18152520 - 6 Aug 2026

Viewed by 520

Abstract

Axillary lymph node staging remains a cornerstone of the surgical management of breast cancer. Conventional axillary lymph node dissection (ALND) has historically been the standard procedure for evaluating nodal involvement; however, it is associated with significant morbidity, including lymphedema, sensory disturbances, and reduced [...] Read more.

Axillary lymph node staging remains a cornerstone of the surgical management of breast cancer. Conventional axillary lymph node dissection (ALND) has historically been the standard procedure for evaluating nodal involvement; however, it is associated with significant morbidity, including lymphedema, sensory disturbances, and reduced shoulder mobility. Over the past few decades, minimally invasive surgery has demonstrated clear benefits in multiple surgical fields, particularly in reducing postoperative morbidity, improving recovery, and enhancing cosmetic outcomes. In breast surgery, these principles have been progressively incorporated into clinical practice. Endoscopic techniques were first introduced in the late 1990s as a minimally invasive alternative to axillary lymph node dissection. Early studies have demonstrated the technical feasibility of endoscopic axillary lymphadenectomy (EALND), reporting adequate lymph node retrieval and acceptable perioperative outcomes. Although the widespread adoption of sentinel lymph node biopsy and the progressive de-escalation of axillary surgery have limited the diffusion of this approach, the potential advantages of minimally invasive techniques appear to be applicable to axillary surgery. In recent years, minimally invasive approaches, including endoscopic and robot-assisted procedures, have been expanded in breast surgery and are now being explored for axillary management. Advances in instrumentation, optics, and imaging technologies, such as fluorescence, have improved surgical visualization and may facilitate safer and more precise dissection of axillary structures. This review summarizes the historical development, technical evolution, and current evidence regarding endoscopic axillary lymphadenectomy for breast cancer. Furthermore, we discuss the potential role of this approach in the modern era of axillary de-escalation and highlight the emerging technologies that may contribute to the future development of minimally invasive axillary surgery. Full article

(This article belongs to the Special Issue Minimally Invasive and Innovative Approaches in Breast Cancer Surgery: Techniques and Outcomes)

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14 pages, 1373 KB

Open AccessArticle

Human Cytomegalovirus Suppresses Estrogen and Progesterone Receptor Expression in Hormone Receptor-Positive Breast Cancer Cells: Implications for Endocrine Resistance

by Erica C. Garcia, Ian J. LaRue, Nathan D. Griggs and Juliet V. Spencer

Cancers 2026, 18(15), 2519; https://doi.org/10.3390/cancers18152519 - 6 Aug 2026

Viewed by 404

Abstract

Background: Hormone receptor-positive breast cancer depends on estrogen and progesterone signaling, yet factors that modulate hormone receptor expression within tumors remain incompletely understood. Human cytomegalovirus (HCMV), a widespread herpesvirus detected in breast tumors, has been associated with reduced expression of estrogen receptor-α (ERα) [...] Read more.

Background: Hormone receptor-positive breast cancer depends on estrogen and progesterone signaling, yet factors that modulate hormone receptor expression within tumors remain incompletely understood. Human cytomegalovirus (HCMV), a widespread herpesvirus detected in breast tumors, has been associated with reduced expression of estrogen receptor-α (ERα) and progesterone receptor (PR), but a direct causal relationship has not been established. Methods: ER+/PR+ breast cancer cell lines MCF-7 and T47D were infected with HCMV in vitro. ERα and PR protein levels were assessed by immunoblotting, and transcript levels of ESR1 and PGR were quantified by qPCR. To determine whether virus replication was required, parallel experiments used UV-inactivated HCMV. Results: HCMV infection resulted in a marked reduction in ERα and PR protein levels in both cell lines, accompanied by decreased ESR1 and PGR transcript levels by 48 h post-infection. Notably, UV-inactivated HCMV produced a comparable suppression of hormone receptor expression, indicating that viral gene expression and productive replication are not required for this effect. Conclusions: These findings indicate that HCMV exposure suppresses ERα and PR expression in breast cancer cells through a replication-independent mechanism. This effect suggests that viral components or host responses to infection may alter hormone receptor signaling within tumors, with potential implications for hormone receptor signaling and endocrine therapy responsiveness that warrant further investigation. Together, these results identify HCMV as a previously underrecognized modulator of hormone receptor pathways in breast cancer. Full article

(This article belongs to the Section Molecular Cancer Biology)

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21 pages, 1569 KB

Open AccessReview

Tumor Progression, Parallel Mechanisms and Therapeutic Targets

by Leif Håkansson, Pontus Dunér and Annika Håkansson

Cancers 2026, 18(15), 2518; https://doi.org/10.3390/cancers18152518 - 6 Aug 2026

Viewed by 405

Abstract

Cancer progression is driven by early dysregulation of the immune system and tumor-intrinsic mechanisms. Hypoxia, lactate accumulation and IL-6 signaling induce highly overlapping tumor-promoting effects, including angiogenesis, epithelial–mesenchymal transition, metastasis, immune evasion and treatment resistance, suggesting that these pathways interact and amplify one [...] Read more.

Cancer progression is driven by early dysregulation of the immune system and tumor-intrinsic mechanisms. Hypoxia, lactate accumulation and IL-6 signaling induce highly overlapping tumor-promoting effects, including angiogenesis, epithelial–mesenchymal transition, metastasis, immune evasion and treatment resistance, suggesting that these pathways interact and amplify one another. This parallel activation complicates therapeutic targeting, as inhibition of one pathway may be compensated for by another. Increased proteolytic activity emerges early during tumor development and profoundly alters immune regulation. We recently identified a protease-generated albumin fragment, the IL-6-inducing factor (IL-6IF), which triggers pathological IL-6 production. IL-6 in turn enhances both HIF-1α expression and nuclear translocation, promotes glycolysis and lactate production, and forms positive feedback loops with STAT3 and multiple signaling pathways. Together, these mechanisms integrate into a self-sustaining IL-6/HIF-1α/STAT3 axis that drives tumor progression and suppresses anti-tumor immunity. The strong overlap among IL-6, its enhancing loops and hypoxia-driven mechanisms highlights IL-6 as a central regulator of metabolic and immunological reprogramming in cancer. However, a broad IL-6 blockade can impair physiological immune function. Selective inhibition of IL-6IF offers a novel strategy to prevent pathological IL-6 production while preserving physiological IL-6-dependent immune function required for effective tumor control. Reducing pathologically enhanced IL-6 synthesis by targeting IL-6IF, therefore, might represent a potential therapeutic approach to disrupt multiple tumor-promoting pathways simultaneously and may thereby improve responsiveness to cancer immunotherapy. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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19 pages, 2703 KB

Open AccessArticle

CDCA4 Promotes Lipid Metabolism in Triple-Negative Breast Cancer Through Activation of the SESN2/mTOR/SREBP1 Pathway

by Jia Qi, Ming Cai, Xiaowen Wang, Peng Zhang, Jiani Wang, Jiezhong Wu, Weiling Huang, Wenxuan Wu, Kunpeng Hu and Xiaoyuan Liang

Cancers 2026, 18(15), 2517; https://doi.org/10.3390/cancers18152517 - 6 Aug 2026

Viewed by 353

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. The molecular drivers of its progression and metabolic reprogramming remain unclear. Here, we identify cell division cycle-associated 4 (CDCA4) as a novel oncogenic driver in TNBC. Analysis of the TCGA-BRCA dataset, [...] Read more.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. The molecular drivers of its progression and metabolic reprogramming remain unclear. Here, we identify cell division cycle-associated 4 (CDCA4) as a novel oncogenic driver in TNBC. Analysis of the TCGA-BRCA dataset, including 1085 breast cancer tissues and 112 normal tissues, showed that CDCA4 expression was significantly upregulated in breast cancer tissues. Subgroup analysis of TCGA-BRCA samples further showed higher CDCA4 expression (fold change = 1.707) in TNBC than in non-TNBC samples [TNBC, n = 116; non-TNBC, n = 984]. Survival analysis demonstrated that high CDCA4 expression was associated with poorer overall survival, with a hazard ratio of 1.54 (log-rank p = 0.0053). Functional assays demonstrated that CDCA4 knockdown suppresses proliferation, migration, invasion, and tumor growth in vitro and in vivo, whereas overexpression exerts opposite effects. RNA-sequencing revealed that CDCA4-regulated genes are enriched in lipid metabolism and mTOR signaling pathways. Mechanistically, CDCA4 depletion reduces intracellular lipids and the expression of lipogenic enzymes (FASN, ACC1). We show that CDCA4 activates mTOR and increases the nuclear active form of SREBP1, enhancing its promoter occupancy. Pharmacological mTOR inhibition reverses CDCA4-induced malignancy and metabolic alterations. Furthermore, Our findings suggest that SESN2 may contribute to CDCA4-mediated activation of mTOR signalling. SESN2 knockdown attenuates mTOR signaling and negates the pro-tumorigenic effects of CDCA4 overexpression. Collectively, these findings demonstrate that CDCA4 drives TNBC progression and lipid reprogramming via the SESN2/mTOR/SREBP1 axis, positioning CDCA4 as a potential prognostic biomarker and therapeutic target. Full article

(This article belongs to the Section Cancer Pathophysiology)

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19 pages, 2759 KB

Open AccessArticle

Tracking Technological Change in Liver Surgery: Robotic Adoption and Case-Mix Evolution in the I Go MILS Registry

by Luca Ruotolo, Alessandro Ferrero, Andrea Ruzzenente, Felice Giuliante, Vincenzo Mazzaferro, Umberto Cillo, Salvatore Gruttadauria, Fabrizio Di Benedetto, Giorgio Ercolani, Matteo Ravaioli, Giuseppe Maria Ettorre, Andrea Belli, Giovanni Vennarecci, Raffaele Dalla Valle, Elio Jovine, Francesca Ratti and on behalf of the I Go MILS Collaborative Group

Cancers 2026, 18(15), 2516; https://doi.org/10.3390/cancers18152516 - 6 Aug 2026

Viewed by 389

Abstract

Background: The adoption of robotic surgery in minimally invasive liver surgery has accelerated globally in the last decade, yet its impact on clinical outcomes and the associated benefits remain to be explored. Methods: The study analyzed 8928 minimally invasive liver resections [...] Read more.

Background: The adoption of robotic surgery in minimally invasive liver surgery has accelerated globally in the last decade, yet its impact on clinical outcomes and the associated benefits remain to be explored. Methods: The study analyzed 8928 minimally invasive liver resections recorded in the I Go MILS registry between 2015 and 2025. Temporal trends in surgical approach, Pringle maneuver utilization, conversion to open surgery, and postoperative morbidity were assessed using Cochran–Armitage and Spearman tests. Case-mix evolution was quantified by the Kawaguchi–Gayet difficulty score. Results: Robotic utilization increased monotonically from 10.4% to 42.2%, while fully laparoscopic procedures declined from 89.6% to 57.8%. Despite this transition, aggregate conversion and morbidity showed no significant temporal trends. Stratified analysis demonstrated lower observed conversion rates in the robotic group and a progressively narrowing difference in morbidity. Overall case-mix complexity increased significantly, driven exclusively by the laparoscopic arm, while the robotic case mix remained structurally stable. Conclusions: Aggregate outcome stability during the robotic transition suggests progressive case-mix complexification rather than technological stagnation. The robotic platform seems to be associated with an apparent conversion advantage; its higher observed morbidity may be attributable to structural differences in operative difficulty. Robotics act not as a substitute for laparoscopy but as a complementary approach applied to more complex resections. Full article

(This article belongs to the Special Issue Surgical Treatment and Prognosis of Hepato-Biliary and Pancreatic Tumors—the Role of Minimally Invasive Surgery)

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24 pages, 2480 KB

Open AccessArticle

Primary Soft Tissue Sarcomas of the Extremities: A Nationwide Retrospective Cohort Study of Histology-Specific Outcomes and Prognostic Factors

by Marko Novak, Andraž Perhavec, Barbka Novak Supe, Olga Blatnik, Marija Skoblar Vidmar, Mojca Unk, Sonja Kramer, Saša Marušič and Manuel Ramanović

Cancers 2026, 18(15), 2515; https://doi.org/10.3390/cancers18152515 - 5 Aug 2026

Viewed by 909

Abstract

Background/Objectives: The aim of this study was to determine the oncologic outcomes for adult patients with primary extremity soft tissue sarcoma (ESTS) treated at the sarcoma referral center in the Republic of Slovenia. Methods: Patients from a prospectively maintained institutional database [...] Read more.

Background/Objectives: The aim of this study was to determine the oncologic outcomes for adult patients with primary extremity soft tissue sarcoma (ESTS) treated at the sarcoma referral center in the Republic of Slovenia. Methods: Patients from a prospectively maintained institutional database treated between January 2009 and December 2023 were retrospectively analyzed. The cohort was stratified into a high-risk group (HRG) and a low-risk group (LRG). Survival analyses focused on the HRG. Multivariable Cox models were constructed for local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS), and predictors of major wound complications were evaluated using multivariable logistic regression. Results: Among 315 included patients, 242 (76.8%) were in the HRG. In this group the median age was 61.5 years, 82.6% of tumors were in the lower extremity, and median tumor size was 9.0 cm. The most common histological subtype was undifferentiated pleomorphic sarcoma (28.5%). Clear margins were achieved in 86.8%, major postoperative complications occurred in 19.0%, and 60.7% of patients underwent radiotherapy. Local recurrence developed in 11.2%, regional recurrence in 5.0%, and distant metastasis in 32.6%. The corresponding 5-year overall survival, disease-specific survival, LRFS, and DMFS were 69.8%, 73.7%, 87.9%, and 66.8% in the HRG, respectively. In the LRG, only one local recurrence occurred and the 5-year LRFS was 100.0%. Preoperative radiotherapy showed a borderline association with major wound complications in the HRG (OR 2.70, 95% CI 1.00–7.28, p = 0.050). Tumor grade and size remained independent predictors of distant metastases, whereas margin status was not significantly associated with LRFS or DMFS. The primary amputation rate in the whole series was 2.9%. Conclusions: Treatment of primary ESTS patients in a specialized national referral cancer center achieved good overall survival (69.8%), a high limb-salvage rate (97.1%), and good local control, affirming that routine primary amputation is rarely needed. Outcomes in high-risk histologies remained driven mainly by distant metastases and showed clear histology-specific differences, whereas low-risk histologies had excellent outcomes with surgery alone. Preoperative radiotherapy was associated with a higher risk of major wound complications. Full article

(This article belongs to the Section Cancer Survivorship and Quality of Life)

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16 pages, 1725 KB

Open AccessSystematic Review

Predicting Therapeutic Response to Antibody-Drug Conjugates Using Targeted PET Imaging: A Systematic Review

by David Mourath, Nour Susaeg Romdhani, Viveka Bergman, Jonathan Siikanen, Thuy A. Tran, Ali Alhuseinalkhudhur, Anna Kistner and Renske Altena

Cancers 2026, 18(15), 2514; https://doi.org/10.3390/cancers18152514 - 5 Aug 2026

Viewed by 524

Abstract

Background: Antibody-drug conjugates (ADCs) are gaining rapidly expanding clinical utility, with a growing number of approved indications across compounds that differ in target antigen, payload mechanism, and linker design. However, treatment response remains heterogeneous, and predictive biomarkers to identify patients most likely to [...] Read more.

Background: Antibody-drug conjugates (ADCs) are gaining rapidly expanding clinical utility, with a growing number of approved indications across compounds that differ in target antigen, payload mechanism, and linker design. However, treatment response remains heterogeneous, and predictive biomarkers to identify patients most likely to benefit are limited. Given that ADC efficacy depends on sufficient target antigen expression and distribution across tumor lesions, positron emission tomography (PET) imaging offers a unique opportunity to non-invasively assess whole-body target availability. We therefore conducted a systematic literature review to evaluate the relationship between PET-measured tumor antigen expression and the therapeutic response to ADCs targeting the same antigen. Method: A systematic comprehensive search of PubMed, EMBASE and Web of Science databases was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, using terms related to targeted PET, ADC treatment and response assessment. Article screening, eligibility assessment, and data extraction were performed independently using predefined criteria by two reviewers. Disagreements were resolved by consensus. Results: A total of 5628 records were identified. After removing duplicates, 4323 records were screened by title and abstract. Fifty-eight underwent full-text review and seven were included in the final review. Four trials investigated human epidermal growth factor receptor 2 (HER2)-targeted therapy, one Nectin-4, one mesothelin and one STEAP1. In all HER2- and Nectin-4-related trials, patients with a higher uptake on targeted PET had a higher probability of responding to targeted treatment. Included trials were generally small and had a moderate risk of bias. Conclusion: Targeted PET imaging showed potential to predict treatment response in trials evaluating clinically active agents. Additional clinical trials across a broader range of targets, along with standardized acquisition protocols and harmonized study designs, are needed to enable the integration of this technique into clinical practice and ultimately translate its benefits to patients. Full article

(This article belongs to the Special Issue Targeted Radiotracers for Molecular Imaging and Therapy in Cancer)

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15 pages, 419 KB

Open AccessReview

The Great Debate: CAR-T-Cell Therapy Versus Bispecific Antibodies in B-Cell Lymphoma

by Massimo Martino, Violetta Marafioti, Martina Pitea, Gaetana Porto, Giorgia Policastro, Filippo Antonio Canale, Virginia Naso and Caterina Alati

Cancers 2026, 18(15), 2513; https://doi.org/10.3390/cancers18152513 - 5 Aug 2026

Viewed by 1536

Abstract

Background: The treatment paradigm for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) has undergone significant change with the advent of CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies and CD20 × CD3 bispecific antibodies (BsAbs). Although both approaches have shown high response rates in single-arm [...] Read more.

Background: The treatment paradigm for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) has undergone significant change with the advent of CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies and CD20 × CD3 bispecific antibodies (BsAbs). Although both approaches have shown high response rates in single-arm studies, the absence of prospective randomized head-to-head comparisons has resulted in true clinical equipoise. Methods: A narrative synthesis was conducted, incorporating pivotal and updated phase 2 and 3 trial data, real-world evidence, and published meta-analyses. Results: In the second-line setting, CAR-T therapy demonstrates superior event-free survival, progression-free survival, and overall survival compared to standard-of-care chemo-transplant regimens. In the third-line setting, a pooled meta-analysis indicates significantly higher complete response rates for CAR-T compared with BsAbs, as well as superior 12-month progression-free survival. BsAbs provide immediate availability, greater accessibility, more favorable neurotoxicity profiles, and are feasible for frail or elderly patients. Real-world data show that BsAb complete response rates are consistently lower than those observed in clinical trials, whereas CAR-T real-world effectiveness closely aligns with pivotal trial outcomes. Emerging phase 3 data on fixed-duration and monotherapy bispecific regimens suggest that a genuine, if less mature, curative fraction may also be achievable among BsAb-treated complete responders. Conclusions: CAR-T therapy remains the standard of care for fit, eligible patients with R/R LBCL in second- and third-line settings with curative intent, providing superior depth and durability of response and a growing potential for long-term cure. BsAbs constitute a critical therapeutic alternative for patients ineligible for CAR-T, those with rapidly progressive disease, frail or elderly individuals, and as bridging strategies. A patient-centered, scenario-specific clinical decision framework is recommended. Full article

(This article belongs to the Special Issue Significance of CAR T-Cell Therapy in Aggressive B-Cell Lymphoma Treatment)

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19 pages, 3131 KB

Open AccessArticle

Surgical Intensity and Survival After Surgery for Extradural Spinal Metastases: Mechanical Instability, Tumor Biology, and Systemic Reserve

by Aydin Talat Baydar, Muhammed Bayindir, Aysenur Coskun Baydar and Baran Taskala

Cancers 2026, 18(15), 2512; https://doi.org/10.3390/cancers18152512 - 5 Aug 2026

Viewed by 277

Abstract

Background/Objectives: Surgery for extradural spinal metastases must balance neurologic and mechanical goals against limited survival. We evaluated whether a predefined three-tier surgical-intensity classification aligned with established measures of operative burden and whether intensity was associated with 90-day mortality or overall survival. Methods: This [...] Read more.

Background/Objectives: Surgery for extradural spinal metastases must balance neurologic and mechanical goals against limited survival. We evaluated whether a predefined three-tier surgical-intensity classification aligned with established measures of operative burden and whether intensity was associated with 90-day mortality or overall survival. Methods: This retrospective cohort included 141 adults with extradural spinal metastases operated on between June 2020 and December 2025. Surgical intensity was classified as low, moderate, or high. SMII was calculated for all patients as a secondary convergent construct measure. Firth penalized logistic regression and Cox regression adjusted for performance status, albumin, and tumor biology. Results: There were 37 low-, 39 moderate-, and 65 high-intensity procedures. Median SMII increased from 6 [5–11] to 14 [11.5–18.5] and 23 [18–28] across the three groups (p < 0.001; Spearman ρ = 0.711). High-intensity surgery was concentrated among unstable SINS lesions and was associated with longer operative time, transfusion, and hospitalization. Ninety-day mortality was 24.3%, 12.8%, and 23.1% for low-, moderate-, and high-intensity procedures, respectively. High intensity was not statistically associated with 90-day mortality (adjusted OR 0.81, 95% CI 0.28–2.36) or overall survival (adjusted HR 1.08, 95% CI 0.65–1.80). ECOG ≥ 3 and aggressive solid/unknown tumor biology were associated with worse outcomes. Conclusions: The intensity classification showed strong convergent validity with SMII and perioperative burden. Within this surgically selected cohort, intensity was not independently associated with early mortality or overall survival, although clinically meaningful differences cannot be excluded. Operative magnitude should be interpreted alongside mechanical need, systemic reserve, and tumor biology. Full article

(This article belongs to the Special Issue Surgical Strategies in Neuro-Oncology: Optimizing Outcomes for Brain and Spinal Tumors)

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23 pages, 17021 KB

Open AccessArticle

Immunological and Clinical Outcomes Associated with Histotripsy Ablation in Spontaneously Occurring Canine Osteosarcoma; Veterinary Clinical Trial Results

by Alayna. N. Hay, Lauren Ruger, Elliana R. Vickers, Sheryl Coutermarsh-Ott, Eli Vlaisavljevich and Joanne Tuohy

Cancers 2026, 18(15), 2511; https://doi.org/10.3390/cancers18152511 - 5 Aug 2026

Viewed by 568

Abstract

Background: Osteosarcoma (OS) is a devasting bone cancer that occurs primarily in pediatric patients, and pet dogs, and treatment options have not advanced in decades. There is a profound need for advancement of treatment options to improve patient prognosis given the grim 70% [...] Read more.

Background: Osteosarcoma (OS) is a devasting bone cancer that occurs primarily in pediatric patients, and pet dogs, and treatment options have not advanced in decades. There is a profound need for advancement of treatment options to improve patient prognosis given the grim 70% 5-year survival rate for human patients, and 10–12-month median survival for canine patients. A major hurdle in advancing treatment options is overcoming the immunosuppressive tumor microenvironment to mitigate metastatic disease progression—the leading cause of mortality in OS patients. Methods: We investigated the ability of a mechanical focused ultrasound ablation modality, histotripsy, to induce acute immunomodulation in canine patients with spontaneously occurring OS. Results: Immunomodulation was evident locally and systemically. Tumor gene signatures indicated upregulation of pro-inflammatory signaling pathways and T-cell receptor signaling, and B-cell activation, and systemically, increased monocyte activation was observed within 5 days post-histotripsy ablation. A subset of patients who received histotripsy prior to definitive standard-of-care exceeded the reported expected median survival time of 10–12 months for canine OS patients that received definitive standard-of-care only. Conclusions: Our results demonstrate the promising potential of histotripsy to overcome the immunosuppressive tumor microenvironment. Full article

(This article belongs to the Special Issue Ultrasound for Cancer Therapy)

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21 pages, 1690 KB

Open AccessReview

Pathological Pathways of Olfactory Neuroblastoma: From Molecular Mechanisms to Targeted Therapy: A Narrative Review

by Wenqiao Zhou, Xingchen Liu, Junying Hu, Yu Chen, Feng Liu and Bing Zhong

Cancers 2026, 18(15), 2510; https://doi.org/10.3390/cancers18152510 - 5 Aug 2026

Viewed by 549

Abstract

Olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma, is a rare malignant tumor arising from the olfactory epithelium of the sinonasal tract. Surgery combined with radiotherapy remains the standard treatment for localized disease, whereas chemotherapy is mainly used in advanced or recurrent cases. However, [...] Read more.

Olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma, is a rare malignant tumor arising from the olfactory epithelium of the sinonasal tract. Surgery combined with radiotherapy remains the standard treatment for localized disease, whereas chemotherapy is mainly used in advanced or recurrent cases. However, recurrent and metastatic ONB continues to present major therapeutic challenges, and traditional staging and histological grading systems cannot fully explain the marked differences in clinical behavior among patients. The primary objective of this review is to summarize recent advances in the molecular pathology, tumor microenvironment (TME), and emerging targeted therapeutic strategies in ONB. Emerging genomic and transcriptomic studies suggest that ONB comprises biologically heterogeneous tumors with distinct molecular and transcriptional programs associated with proliferation, neuroendocrine differentiation, angiogenesis, and stromal remodeling. Furthermore, we explore the increasing attention directed toward the TME, including immune-cell infiltration, angiogenic signaling, and immune checkpoint expression, which may influence therapeutic response. These molecular findings have generated interest in several potential targeted treatment strategies, including peptide receptor radionuclide therapy (PRRT), anti-angiogenic therapy, epigenetic-targeted therapy, immunotherapy, and DNA-damage-response-targeted approaches. Ultimately, although the current evidence remains limited because of the rarity of the disease, novel therapeutic strategies for ONB are emerging. In addition to summarizing the current landscape, this review discusses the translational challenges and future directions for precision oncology and biomarker-driven therapy, aiming to provide insights for improving individualized patient management. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: From Diagnosis to Therapy (2nd Edition))

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19 pages, 2679 KB

Open AccessArticle

Ex Vivo Line-Field Confocal Optical Coherence Tomography and Ex Vivo Fusion Confocal Microscopy for Lateral-Margin Assessment of Basal Cell Carcinoma in Correlation with Histopathology: A Prospective Pilot Diagnostic-Accuracy Study

by Kristina Fünfer, Marco Mozaffari, Hanna Illium, Sophia Schlingmann, Oliver Mayer, Maximillian Deußing, Elke Sattler, Julia Welzel and Sandra Schuh

Cancers 2026, 18(15), 2509; https://doi.org/10.3390/cancers18152509 - 5 Aug 2026

Viewed by 363

Abstract

Background/Objectives: Rapid optical assessment of freshly excised basal cell carcinoma (BCC) specimens may shorten the interval between excision and margin evaluation. This prospective pilot study estimated the diagnostic performance of ex vivo line-field confocal optical coherence tomography (LC-OCT) for detecting residual BCC [...] Read more.

Background/Objectives: Rapid optical assessment of freshly excised basal cell carcinoma (BCC) specimens may shorten the interval between excision and margin evaluation. This prospective pilot study estimated the diagnostic performance of ex vivo line-field confocal optical coherence tomography (LC-OCT) for detecting residual BCC at lateral surgical margins, using histopathology as the reference standard. Methods: Fifty-five clinically suspicious lesions from 48 patients were examined at two centers. Results were analyzed for the complete cohort and for a post-training inclusion phase comprising 32 lesions from 31 patients. Overall lesion-level consensus classifications were recorded separately from classifications of the four clock-face quadrants. Lesions with a negative overall LC-OCT assessment and at least one non-evaluable quadrant were classified as indeterminate and excluded from the primary lesion-level analysis. Thirteen lesions also underwent exploratory ex vivo fusion confocal microscopy (evFCM). Results: In the inclusion phase, 125 of 128 quadrants were evaluable. Thirteen true-positive, 106 true-negative, 2 false-negative, and 4 false-positive quadrant results yielded 86.7% sensitivity, 96.4% specificity, and 95.2% accuracy. At the lesion level, 2 of 32 results were indeterminate. Among the remaining 30 lesions, LC-OCT yielded 5 true-positive, 22 true-negative, 2 false-negative, and 1 false-positive results, corresponding to 71.4% sensitivity, 95.7% specificity, and 90.0% accuracy. The evFCM analysis was descriptive because the subset was small and nonconsecutive. Conclusions: Ex vivo LC-OCT showed promising specificity and overall accuracy for assessing lateral BCC margins after training. The limited number of margin-positive lesions, indeterminate results, clustered quadrant data, and absence of systematic deep-margin imaging require cautious interpretation. LC-OCT should not replace histopathological margin assessment on the basis of the present data. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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18 pages, 3894 KB

Open AccessSystematic Review

Mapping Misconceptions in Neuroendocrine Tumor Nomenclature: A Scoping Review of National Database Studies and Clinical Implications

by Theo F. Hanson, Margaret Hua, Jorge Zarate Rodriguez, Lauren H. Yaeger, Shreya Rao Chilukuri, Nikolaos A. Trikalinos and Chet W. Hammill

Cancers 2026, 18(15), 2508; https://doi.org/10.3390/cancers18152508 - 5 Aug 2026

Viewed by 383

Abstract

In 2010, the World Health Organization (WHO) standardized neuroendocrine neoplasm terminology, dividing these tumors by differentiation into well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Registries such as the Surveillance, Epidemiology, and End Results (SEER) program and the National Cancer Database (NCDB) store [...] Read more.

In 2010, the World Health Organization (WHO) standardized neuroendocrine neoplasm terminology, dividing these tumors by differentiation into well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Registries such as the Surveillance, Epidemiology, and End Results (SEER) program and the National Cancer Database (NCDB) store legacy codes predating this framework, raising concern that registry-based research carries nomenclature errors into the clinical literature. We performed a scoping review of research published in 2012–2022 that used SEER and/or the NCDB to study gastroenteropancreatic neuroendocrine tumors, charting 170 articles (from 1079 citations) against the 2010 classification, with forward citation analysis (OpenAlex, Semantic Scholar) measuring downstream citation exposure. Of 141 assessable studies, 88% (n = 124) applied the nomenclature inaccurately: 82.3% included poorly or undifferentiated neoplasms within neuroendocrine tumor cohorts (mean 18.7% of the cohort) and 9.9% conflated database differentiation grade with WHO proliferation grade; appropriate usage did not improve over time. These discordant studies accumulated 7323 citations across 5145 works, with 87.9% cited by at least one review (1075 distinct reviews) and six cited by major guidelines (NCCN, ESMO, ENETS). Across research published from 2012 to 2022, nomenclature discordance was widespread, persistent throughout the study period, and present in studies frequently cited by the secondary and guideline literature. Because these cohorts incorporate more aggressive and poorly or undifferentiated neoplasms, their aggregate outcome estimates are likely biased toward a poorer prognosis, potentially overstating the aggressiveness of well-differentiated neuroendocrine tumors, particularly for prognostic estimates; this review characterized cohort composition rather than quantifying the effect on any individual study’s outcomes, and whether this bias has, in turn, affected clinical decision-making was not assessed here and remains a hypothesis for future work. Journals and guideline panels should require explicit alignment with current WHO definitions for registry-based studies. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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48 pages, 1907 KB

Open AccessReview

Targeting β-Adrenergic Signaling in Colorectal Cancer: Molecular Mechanisms and Therapeutic Potential of β-Blockers

by Zuzanna Rogacz, Wiktoria Weronika Pacuła, Wiktor Janas, Magda Markiewka, Paulina Wala, Marcel Madej and Barbara Strzałka-Mrozik

Cancers 2026, 18(15), 2507; https://doi.org/10.3390/cancers18152507 - 5 Aug 2026

Viewed by 831

Abstract

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide despite substantial advances in surgery, chemotherapy, targeted therapies, and immunotherapy. The limited efficacy of current treatment strategies in advanced disease and the emergence of therapeutic resistance highlight the [...] Read more.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide despite substantial advances in surgery, chemotherapy, targeted therapies, and immunotherapy. The limited efficacy of current treatment strategies in advanced disease and the emergence of therapeutic resistance highlight the urgent need for novel adjunctive therapeutic approaches. Increasing evidence indicates that chronic stress and sustained activation of β-adrenergic signaling promote colorectal tumor initiation, progression, angiogenesis, metastatic dissemination, and immune evasion, thereby identifying this pathway as a potential therapeutic target. Drug repurposing has emerged as an attractive strategy for accelerating the development of new anticancer therapies by identifying novel applications for clinically approved drugs with well-established safety profiles. Among these, β-blockers have gained considerable attention because of their ability to inhibit β-adrenergic signaling and modulate multiple oncogenic pathways implicated in CRC progression. Although accumulating preclinical and observational clinical evidence suggests that β-blockers may possess anticancer potential, the underlying molecular mechanisms and their translational relevance have not yet been comprehensively integrated. This review provides a critical overview of the current evidence regarding the therapeutic potential of β-blockers in CRC by integrating findings from preclinical and clinical studies. Particular emphasis is placed on the regulation of key signaling pathways, including cAMP/PKA/CREB, PI3K/AKT/mTOR, and RAS/RAF/MEK/ERK, as well as on the effects of β-blockers on tumor cell proliferation, apoptosis, angiogenesis, epithelial–mesenchymal transition, metastasis, and modulation of the tumor microenvironment and antitumor immune responses. However, significant barriers limit the translation of these findings into routine clinical practice, including the limited representativeness of preclinical models, potential hemodynamic adverse effects, and the inherent limitations of observational studies. Importantly, owing to the lack of prospective randomized clinical trials, the current evidence remains insufficient to establish the clinical efficacy of β-blockers in CRC. Although β-blockers possess several characteristics that make them attractive candidates for drug repurposing, including a well-established safety profile, widespread availability, and low cost, further mechanistic studies, prospective randomized clinical trials, and biomarker-based patient stratification are essential to determine their clinical efficacy and define their role in personalized CRC therapy. Full article

(This article belongs to the Collection New Treatment for Colorectal Cancer)

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14 pages, 8805 KB

Open AccessSystematic Review

Radiotherapy Strategies for WHO Grade 1 Meningioma: A Systematic Review and Meta-Analysis Comparing Proton Therapy, Conventional Radiotherapy, and Radiosurgery

by Hazuki Nitta, Masashi Mizumoto, Kazushi Maruo, Yoshiko Oshiro, Yinuo Li, Kenji Kagawa, Takashi Saito, Haruko Numajiri, Kei Nakai, Tetsuo Nonaka and Hideyuki Sakurai

Cancers 2026, 18(15), 2506; https://doi.org/10.3390/cancers18152506 - 5 Aug 2026

Viewed by 517

Abstract

Background/Objectives: The optimal radiotherapy modality for World Health Organization (WHO) Grade 1 meningioma remains uncertain. Proton therapy offers dosimetric advantages through reduced radiation exposure to normal brain tissue, but comparative clinical data across contemporary radiotherapy modalities are limited. We performed a systematic review [...] Read more.

Background/Objectives: The optimal radiotherapy modality for World Health Organization (WHO) Grade 1 meningioma remains uncertain. Proton therapy offers dosimetric advantages through reduced radiation exposure to normal brain tissue, but comparative clinical data across contemporary radiotherapy modalities are limited. We performed a systematic review and meta-analysis comparing local control (LC) outcomes among conventionally fractionated proton therapy (CF-PT), conventionally fractionated photon radiotherapy (CF-Photon RT), Linac-based stereotactic radiosurgery/radiotherapy (Linac-based SRS/SRT), and Gamma Knife radiosurgery (GKRS). Methods: A systematic literature search of PubMed (2000–2024) was conducted to identify studies reporting LC for WHO Grade 1 meningioma treated with CF-PT, CF-Photon RT, Linac-based SRS/SRT, or GKRS. Random-effects meta-analyses were performed to estimate pooled 1- to 5-year LC rates. Random-effects meta-regression analyses were conducted using modality, age, sex, and gross tumor volume (GTV) as covariates. Results: Twenty-four studies comprising 4673 patients were included in the meta-analysis. Median GTVs were larger in the CF-PT and CF-Photon RT cohorts than in the Linac-based SRS/SRT and GKRS cohorts. All modalities achieved excellent LC: 5-year LC rates were 95.9% for CF-PT, 93.0% for CF-Photon RT, 95.3% for Linac-based SRS/SRT, and 89.8% for GKRS. Meta-regression showed no significant association between modality or GTV and LC. In the CF-PT cohort, 5-year overall survival was 93.1%. Conclusions: Major radiotherapy modalities achieved excellent and comparable LC. Notably, CF-PT and CF-Photon RT maintained favorable LC despite being used for larger tumors than stereotactic approaches. Future studies are needed to evaluate long-term tumor control and treatment-related toxicity to define optimal treatment strategies. Full article

(This article belongs to the Special Issue Radiation Therapy for Meningiomas)

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19 pages, 5825 KB

Open AccessReview

Advances in Optical and Fluorescence Imaging for Surgical Management of Thyroid Cancer

by Blackberrie Eddins, Ting-Chun Kuo, Hyungju Kwon, Homan Kang, Maged Henary, Satoshi Kashiwagi, Robert M. Hoffman and Michael Bouvet

Cancers 2026, 18(15), 2505; https://doi.org/10.3390/cancers18152505 - 5 Aug 2026

Viewed by 451

Abstract

Background/Objectives: The majority of thyroid cancer patients are diagnosed with papillary thyroid cancer. A complete R0 resection significantly lowers cancer recurrence risk for high-risk papillary thyroid cancer but can be difficult to achieve because tumor margins are not easily visualized. The purpose of [...] Read more.

Background/Objectives: The majority of thyroid cancer patients are diagnosed with papillary thyroid cancer. A complete R0 resection significantly lowers cancer recurrence risk for high-risk papillary thyroid cancer but can be difficult to achieve because tumor margins are not easily visualized. The purpose of the present narrative review is to describe current work and future directions in fluorescence-guided thyroid cancer surgery. Methods: PubMed and Google Scholar were used to identify 45 articles that focused on fluorescence labeling and imaging of thyroid cancer published through February 2026 using the search terms “thyroid cancer” AND (“fluorescence imaging,” OR “NIR imaging” OR “optical imaging”) OR “fluorescence guided thyroidectomy”. Standalone abstracts and publications not available in English were excluded. Results: 17 fluorescent probes were shown to visualize tumor margins and micrometastases, 3 probes were able to visualize nerves, and 2 probes targeted lymph nodes. Most studies were done using animal models. Two probes (EMI-137, which targets tumors, and bevonescein, which targets nerves) were tested in clinical trials with good safety profiles. Conclusions: Several tumor-targeted fluorophores and optical imaging strategies have shown promise for thyroid cancer localization, margin assessment, lymph node evaluation, and nerve visualization; however, most remain preclinical, and clinical utility will require standardized dosing, imaging thresholds, safety assessment, and outcome-based validation with multicenter clinical trials. Full article

(This article belongs to the Section Methods and Technologies Development)

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17 pages, 1538 KB

Open AccessArticle

Post-Treatment Persistent Erythrocytosis in Patients with Hodgkin Lymphoma: Molecular Mechanisms Underlying the Pathogenesis of Erythrocytosis

by Derya Koyun, Seher Yüksel, Sinem Civriz Bozdağ, Timur Tuncalı, Işınsu Kuzu and Muhit Özcan

Cancers 2026, 18(15), 2504; https://doi.org/10.3390/cancers18152504 - 5 Aug 2026

Viewed by 465

Abstract

Background: Post-treatment erythrocytosis (PT-E⁺)—an increase in red blood cell counts after therapy—is an uncommon but reproducible finding in a subset of Hodgkin lymphoma (HL) survivors, and its biological basis remains undefined. Methods: A targeted DNA sequencing panel of 33 genes was [...] Read more.

Background: Post-treatment erythrocytosis (PT-E⁺)—an increase in red blood cell counts after therapy—is an uncommon but reproducible finding in a subset of Hodgkin lymphoma (HL) survivors, and its biological basis remains undefined. Methods: A targeted DNA sequencing panel of 33 genes was used at diagnosis and during follow-up in PT-E⁺ patients and HL controls who did not develop erythrocytosis (E⁻; those without increased red blood cells). Germline (inherited) and somatic (acquired) genetic variants were compared, and changes in variant frequency over time were assessed. Results: PT-E⁺ patients had a unique molecular profile. They showed inherited variants in genes that regulate oxygen sensing and red blood cell production (EPAS1, EGLN3, HIF3A, PKLR, SH2B3, and RAB4B-EGLN2). Rare, acquired mutations affecting hypoxia, HIF, and EPO pathways (EGLN1/2/3, EPAS1, HIF1A/3A, VHL, EPO, and PKLR) were also found. These changes did not appear in E⁻ controls, who instead had common clonal hematopoiesis mutations (DNMT3A, TET2, ASXL1, and JAK3). Most somatic variants in the hypoxia pathway in PT-E⁺ patients decreased or disappeared after treatment, which suggests these changes are temporary and influenced by the surrounding environment. Conclusions: PT-E⁺ is biologically different from polycythemia vera and from idiopathic or JAK2-unmutated erythrocytosis. Both inherited risk and HL-related hypoxic or inflammatory stress are present. This supports a two-hit model, in which genetically primed red blood cell pathways respond strongly to disease-related triggers. These results suggest a new way to understand erythrocytosis after HL treatment. Full article

(This article belongs to the Section Molecular Cancer Biology)

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1 pages, 127 KB

Open AccessCorrection

Correction: Furlepa et al. Management of Triple M Syndrome: A Systematic Review with Narrative Synthesis of Immune Checkpoint Inhibitor-Induced Myasthenia Gravis, Myositis and Myocarditis. Cancers 2025, 17, 2063

by Martin Furlepa, Isabella Watts and Aisling S. Carr

Cancers 2026, 18(15), 2503; https://doi.org/10.3390/cancers18152503 - 5 Aug 2026

Viewed by 289

Abstract

In the published publication [...] Full article

15 pages, 2458 KB

Open AccessArticle

Physical Activity Is Associated with Higher Retinal Microvascular Density in Uveal Melanoma and Nevus

by Theresa Walz, Freerk T. Baumann, Katharina Leuchte, Damir Zubac, Philomena Wawer Matos Reimer, Konrad R. Koch and Michael Mendes Wefelnberg

Cancers 2026, 18(15), 2502; https://doi.org/10.3390/cancers18152502 - 4 Aug 2026

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Abstract

Background/Objectives: The aim of the present study was to assess the influence of physical activity on retinal microvascularization in patients with uveal melanoma (UM) and nevus. In addition, vascular differences between tumor and nevus patients as well as the interaction effect of [...] Read more.

Background/Objectives: The aim of the present study was to assess the influence of physical activity on retinal microvascularization in patients with uveal melanoma (UM) and nevus. In addition, vascular differences between tumor and nevus patients as well as the interaction effect of physical activity (PA) and group on retinal microvascular density (MVD) were analyzed. Methods: This cross-sectional, observational clinical study was conducted at the outpatient ophthalmic oncology department at the Center for Integrated Oncology of the University Hospital Cologne (between April 2024 and July 2025). Patients with confirmed uveal melanoma or choroidal nevus were enrolled. Physical activity and retinal MVD via optical coherence tomography angiography were assessed. In addition, regression analyses were performed. Results: A total of 42 participants were enrolled with a mean age of 56.14 (±13.48) years (nevus) and 63.45 (±13.76) years (UM). UM eyes (N = 20) demonstrated significantly reduced MVD in both the superficial and deep layer compared to Nevus (N = 22, all p < 0.001, η² = 0.155–0.190), while UM eyes showed greater mean vessel length (B = 5.54, p = 0.009, η² = 0.104). Physical activity was positively associated with MVD in the superficial layer, including vessel area density (B = 1.07, p = 0.022, η² = 0.133) and vessel length density (B = 0.28, p = 0.028, η² = 0.119), independent of group. No significant associations were found in the deep layer and no interaction effects between group and PA were detected. Conclusions: Our findings suggest that habitual PA is positively associated with retinal MVD in the superficial layer, independent of diagnostic group, and may partially counteract tumor-induced as well as treatment-related microvascular disruption. As a low-risk and accessible intervention, PA holds promise as a supportive strategy in the oncological management of UM. Full article

(This article belongs to the Special Issue Basic and Translational Science in Ocular Oncology)

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16 pages, 310 KB

Open AccessReview

The Role of Direct-Acting Antivirals (DAAs) in Hepatitis C Virus-Associated Lymphoproliferative Disorders

by Cesare Mazzaro, Riccardo Bomben, Laura Gragnani, Marcella Visentini, Paolo Agostinis, Silvia Marri, Anna Linda Zignego and Valter Gattei

Cancers 2026, 18(15), 2501; https://doi.org/10.3390/cancers18152501 - 4 Aug 2026

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Abstract

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, affecting approximately 50 million people worldwide. An estimated 15–30% of individuals with chronic HCV infection progress to cirrhosis, which may subsequently develop into hepatocellular carcinoma. Beyond liver disease, HCV is associated [...] Read more.

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, affecting approximately 50 million people worldwide. An estimated 15–30% of individuals with chronic HCV infection progress to cirrhosis, which may subsequently develop into hepatocellular carcinoma. Beyond liver disease, HCV is associated with a broad spectrum of extrahepatic manifestations, particularly mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). Persistent viral infection induces chronic antigenic stimulation of B lymphocytes, a key pathogenic mechanism underlying the progression from MC to overt B-NHL. These observations have important therapeutic implications and support the use of antiviral therapy as a cornerstone of treatment. The efficacy of direct-acting antivirals (DAAs) has been well established in patients with HCV-related MC and cryoglobulinemic vasculitis. Several studies have shown that DAAs achieve sustained virologic response rates exceeding 90%, often approaching 100% in contemporary cohorts. Viral eradication is frequently associated with clinical and immunological improvement, as well as regression of cryoglobulinemia. Encouraging outcomes have also been reported in patients with HCV-associated indolent B-NHL, particularly marginal zone lymphoma, although confirmation in larger studies with longer follow-up is needed. In patients with HCV-positive aggressive lymphomas, DAAs have been safely administered in combination with immunochemotherapy, yielding promising results. This review summarizes the current evidence on HCV-associated MC and B-NHL and discusses the impact of DAA therapy on the clinical course and management of these disorders. Full article

(This article belongs to the Special Issue Development of Hepatitis C Virus-Related Cancers)

22 pages, 9534 KB

Open AccessArticle

P2RY13-Negative Tumor-Associated Macrophages Promote NETosis and Are Associated with Poor Prognosis Across Multiple Cancers

by Shen Yang, Guangsheng Zhu, Zixuan Hu, Mingbiao Li, Jianfang Wang, Zhanrui Zhang, Jun Chen and Renwang Liu

Cancers 2026, 18(15), 2500; https://doi.org/10.3390/cancers18152500 - 4 Aug 2026

Viewed by 506

Abstract

Background: Neutrophil extracellular traps (NETs) promote tumor progression and immune evasion across multiple cancers. However, the mechanisms governing NET formation (NETosis) within the tumor immune microenvironment remain incompletely understood. Low P2RY13 expression is associated with the pro-tumor activity of neutrophils in lung [...] Read more.

Background: Neutrophil extracellular traps (NETs) promote tumor progression and immune evasion across multiple cancers. However, the mechanisms governing NET formation (NETosis) within the tumor immune microenvironment remain incompletely understood. Low P2RY13 expression is associated with the pro-tumor activity of neutrophils in lung adenocarcinoma. Methods: Pan-cancer bioinformatics analyses were performed, including differential gene expression, prognostic, tumor-infiltrating immune cell, and NET scoring analyses. Single-cell profiling was conducted using the Tumor Immune Single-cell Hub 2 database. Immunohistochemical (IHC) and multiplex immunofluorescence (mIF) staining of tissue microarrays (TMAs) was performed to validate findings in lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), and colorectal cancer (CRC). In vitro validation was conducted using gene modulation, tumor-cell-conditioned medium (CM) education, tumor-associated macrophage (TAM)-like macrophage CM transfer, immunofluorescence staining, and ELISA. Results: Bioinformatics analyses suggested that P2RY13 is frequently dysregulated in multiple cancers and that low P2RY13 expression is associated with poor prognosis and reduced immunotherapy responsiveness. Single-cell analyses revealed that P2RY13 is predominantly expressed in TAMs rather than tumor cells. Macrophages without detectable P2RY13 transcripts were markedly enriched in tumor tissues compared with paired normal tissues, and their high infiltration appeared to be associated with elevated NET scores. Tissue microarray-based IHC and mIF analyses further validated this infiltration pattern in LUAD, LIHC, and CRC. In vitro, CM from P2RY13-silenced, tumor-educated TAM-like macrophages enhanced neutrophil NETosis, whereas P2RY13 re-expression attenuated this effect. Furthermore, TMA staining indicated a positive correlation between P2RY13⁻CD68⁺ TAM infiltration and NET expression in the three malignancies. Conclusions: We identified a potentially conserved NETosis-regulating pattern in multiple cancers in which P2RY13-negative TAMs promote NET formation and are associated with adverse clinical outcomes. These findings suggest a previously unrecognized tumor-promoting mechanism and highlight potential therapeutic targets for cancer treatment. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment: Molecular Mechanisms and Signaling Pathways)

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