Cancers

15 pages, 2473 KB

Open AccessArticle

CV1 Chimpanzee Adenovirus Efficiently Transduces Mesenchymal Stem and Leukemia Cells: Implications for Cellular Targeting and Vector Tropism

by Lorella Tripodi, Maria Vitale, Barbara Izzo, Filippo Scialò, Barbara Lombardo and Lucio Pastore

Cancers 2026, 18(2), 220; https://doi.org/10.3390/cancers18020220 - 9 Jan 2026

Abstract

Objectives: Adenoviruses (Ads) are among the most used vectors for gene therapy; human Ad serotype 5-derived (HuAd5) vectors are the most frequently used for gene transfer applications. However, Ad5 infection is endemic in humans, and 20% of the Western population has neutralizing antibodies [...] Read more.

Objectives: Adenoviruses (Ads) are among the most used vectors for gene therapy; human Ad serotype 5-derived (HuAd5) vectors are the most frequently used for gene transfer applications. However, Ad5 infection is endemic in humans, and 20% of the Western population has neutralizing antibodies (nAbs). Pre-existing immunity against HuAd5 represents a major issue for many gene therapy applications. In our study, we evaluated several Ad serotypes derived from chimpanzees (ChAds) in vitro and in vivo to assess their transduction efficiency in various cell types and tissues. We aimed at identifying Ad serotypes able either to transduce “challenging” cell types or to represent a possible alternative to Ad5-derived vectors with comparable infectivity and tropism. Methods: We evaluated the efficacy of transduction of twelve ChAds vectors expressing enhanced green fluorescent protein (EGFP) in human embryonic kidney cells, as well as human leukemic and human mesenchymal stem cells, using flow cytometry to determine the percentage of EGFP-expressing cells and their mean fluorescent intensity (MFI). We observed the highest transduction efficiency in the serotype CV1 ChAd; therefore, we proceeded to evaluate toxicity and biodistribution in vivo. Results: After in vitro evaluation of twelve ChAds serotypes, we observed that the CV1 serotype was the most efficient in transducing both leukemia cell lines (HL-60 and NB-4) and human mesenchymal stem cells. Furthermore, in vivo analysis of the CV1 serotype induced an inflammatory reaction similar to what was observed after HuAd5 administration. Conclusions: ChAds vectors represent an effective alternative for the transduction of cells resistant to HuAd5 infection, such as mesenchymal stem cells and leukemic cells. In addition, we observed that the CV1 ChAd serotype presented a transduction profile similar to HuAd5 in vitro and induced a similar inflammatory response in vivo; therefore, CV1 ChAd-derived vectors represent an interesting alternative for gene therapy applications. Full article

(This article belongs to the Special Issue New Insights into Cancer Immunotherapy: From Immune Cell to Clinical Practice)

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18 pages, 1407 KB

Open AccessArticle

Protocol Development for the Korean Survey for Cancer Survivorship and Preliminary Analysis of Employment Change’s Impact on Quality of Life and Psychological Health

by Janine Marie Balbedina, Yeol Kim, Hye Joo Jang, Ha Yeong You, Jae Hyun Park, Hyun Woo Lee, Ji Soo Park, Yu Ri Choe and Kyu Won Jung

Cancers 2026, 18(2), 219; https://doi.org/10.3390/cancers18020219 - 9 Jan 2026

Abstract

Background/Objectives: The Korean Survey for Cancer Survivorship (KSCS) aims to comprehensively assess cancer survivors’ health behaviors, quality of life (QoL), and socioeconomic challenges. This study evaluated the feasibility of the KSCS protocol and identified key factors influencing psychological health and QoL among [...] Read more.

Background/Objectives: The Korean Survey for Cancer Survivorship (KSCS) aims to comprehensively assess cancer survivors’ health behaviors, quality of life (QoL), and socioeconomic challenges. This study evaluated the feasibility of the KSCS protocol and identified key factors influencing psychological health and QoL among cancer survivors. Methods: The nationwide survey targeted survivors diagnosed with breast, colorectal, liver, lung, stomach, prostate, and gynecological cancers who had completed active treatment within 1 to 10 years. The respondents were given the option to participate in the survey either online or in-person. The questionnaire has 229 questions, including internationally validated tools such as the EQ-5D-3L, PHQ-9, and GAD-7. Results: A total of 983 cancer survivors completed the survey (92.7% online, 8.3% in-person) and were categorized by post-diagnosis duration. Survivors diagnosed within 1–3 years reported higher rates of moderate-severe depression (11.4% vs. 8.3%), moderate-severe anxiety (5.9% vs. 5.1%), and poorest QoL (63.0% vs. 50.9%) compared to those diagnosed more than 5 years ago. Employment changes, such as loss of job, change of workplace, or work leave, were significantly associated with worse health outcomes, including higher rates of moderate-severe depression (OR = 4.39; 95% CI 2.43–7.96), moderate-severe anxiety (OR = 3.63; 95% CI 1.68–0.88), and having extreme QoL problems (OR = 6.37; 95% CI 2.03–20.00). Conclusions: The KSCS protocol is feasible for nationwide implementation and provides comprehensive data on health, psychological, and socioeconomic challenges among cancer survivors. Preliminary findings highlight employment’s critical role in cancer survivors’ well-being and the need for survivorship care that integrates socioeconomic and clinical factors. Full article

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

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15 pages, 979 KB

Open AccessArticle

Small Bowel Gastrointestinal Stromal Tumors: A 15-Year Cohort Study Focusing on Jejuno-Ileal Site-Specific Outcomes and Prognostic Factors

by Yuichi Kojima, Kentaro Tominaga, Yuzo Kawata, Chizuru Kaneko, Shuhei Kondo, Yoshifumi Shimada, Junji Yokoyama, Toshifumi Wakai and Shuji Terai

Cancers 2026, 18(2), 218; https://doi.org/10.3390/cancers18020218 - 9 Jan 2026

Abstract

Background: Site-specific long-term outcomes, including neurofibromatosis type 1 (NF1), Ki-67 prognostic value, and very late recurrences of small bowel gastrointestinal stromal tumors (GISTs), remain inadequately defined. Methods: This retrospective cohort study investigated the clinical characteristics, diagnostic challenges, and long-term outcomes of patients with [...] Read more.

Background: Site-specific long-term outcomes, including neurofibromatosis type 1 (NF1), Ki-67 prognostic value, and very late recurrences of small bowel gastrointestinal stromal tumors (GISTs), remain inadequately defined. Methods: This retrospective cohort study investigated the clinical characteristics, diagnostic challenges, and long-term outcomes of patients with small bowel GISTs. This retrospective, single-center study (2008–2024) analyzed 27 consecutive patients (average age: 62.2 years) with jejunal/ileal GISTs. Clinicopathologic features, diagnostic yield of balloon-assisted enteroscopy (BAE), treatments, and outcomes were evaluated during a 10.2-year median follow-up period. Recurrence-free survival (RFS) and overall survival (OS) were estimated by Kaplan–Meier with log-rank testing. Ki-67 was assessed using MIB-1; a prespecified 5% cut-off was chosen based on prior evidence. Results: Tumor (mean size, 62.4 mm) sites included the jejunum (74.1%) and ileum (25.9%). NF1 was present in 3/27 (11.1%) patients, all with multiple jejunal tumors. Among the 14 patients who underwent BAE, biopsy was attempted in six and yielded a histological diagnosis in one (16.7%). Six patients had recurrence; two died from disease >10 years postoperatively. Five-year OS and RFS were 91.3% and 68.7%, respectively. Adverse RFS was associated with ileal location (p = 0.03), size ≥ 10 cm (p < 0.001), mitoses > 5/50 high-power fields (p = 0.002), and Ki-67 ≥ 5% (p < 0.001). One patient labeled low risk by conventional models had recurrence with Ki-67 = 10%. Another classified as low risk by conventional models experienced recurrence >10 years after surgery, with a Ki-67 index of 10%. Conclusions: Extended, risk-adapted surveillance may be reasonable for small-bowel GISTs, and it may be beneficial to incorporate Ki-67 (≥5%) into site-based risk stratification. These observations remain hypothesis-generating and require validation in larger, multicenter cohorts and prospective studies. Full article

(This article belongs to the Section Cancer Therapy)

18 pages, 953 KB

Open AccessReview

The Role of Low CD36 Expression in the Development of Non-Small Cell Lung Cancer and Its Potential for Therapy

by Ran Wu, Xiaohong Xu, Danju Luo, Junhua Wu, Xiaona Chang, Chenggong Ma, Bo Huang, Jun Fan and Xiu Nie

Cancers 2026, 18(2), 217; https://doi.org/10.3390/cancers18020217 - 9 Jan 2026

Abstract

Lung cancer remains one of the most prevalent and lethal malignancies worldwide. NSCLC, which constitutes approximately 85% of cases, continues to exhibit a poor prognosis despite advancements in therapeutic interventions, underscoring the urgent necessity to elucidate its molecular mechanisms and identify novel therapeutic [...] Read more.

Lung cancer remains one of the most prevalent and lethal malignancies worldwide. NSCLC, which constitutes approximately 85% of cases, continues to exhibit a poor prognosis despite advancements in therapeutic interventions, underscoring the urgent necessity to elucidate its molecular mechanisms and identify novel therapeutic targets. CD36, a multifunctional transmembrane glycoprotein, is integral to lipid uptake, immune recognition, inflammatory regulation, molecular adhesion, and apoptosis. Increasing evidence implicates CD36 in the progression of various cancers. In the context of lung cancer, CD36 facilitates tumorigenesis through multiple pathways, including the remodeling of tumor cell lipid metabolism, reprogramming of tumor-associated macrophages, and modulation of immune cell functions such as those of Tregs and CD8⁺ T cells. Additionally, CD36 is intricately linked with the function of cancer-associated fibroblasts and the remodeling of the tumor stromal microvasculature. This systematic review synthesizes the mechanisms by which CD36 contributes to NSCLC proliferation, migration, epithelial–mesenchymal transition, and modulation of the tumor microenvironment. Furthermore, we explore emerging therapeutic strategies that target CD36. Regulating CD36 expression effectively intervenes in the malignant behavior of NSCLC, underscoring its potential as a promising therapeutic target and prognostic marker. Full article

(This article belongs to the Section Cancer Therapy)

24 pages, 5341 KB

Open AccessArticle

Molecular Pathology of Advanced NSCLC: Biomarkers and Therapeutic Decisions

by Melanie Winter, Jan Jeroch, Maximilian Wetz, Marc-Alexander Rauschendorf and Peter J. Wild

Cancers 2026, 18(2), 216; https://doi.org/10.3390/cancers18020216 - 9 Jan 2026

Abstract

Background: Advances in molecular pathology have transformed NSCLC (Non-Small Cell Lung Cancer) diagnosis, prognosis, and treatment by enabling precise tumor characterization and targeted therapeutic strategies. We review key genomic alterations in NSCLC, including EGFR (epidermal growth factor receptor) mutations, ALK (anaplastic lymphoma kinase) [...] Read more.

Background: Advances in molecular pathology have transformed NSCLC (Non-Small Cell Lung Cancer) diagnosis, prognosis, and treatment by enabling precise tumor characterization and targeted therapeutic strategies. We review key genomic alterations in NSCLC, including EGFR (epidermal growth factor receptor) mutations, ALK (anaplastic lymphoma kinase) and ROS1 (ROS proto-oncogene 1) rearrangements, BRAF (B-Raf proto-oncogene serine/threonine kinase) mutations, MET (mesenchymal–epithelial transition factor) alterations, KRAS (Kirsten rat sarcoma) mutations, HER2 (human epidermal growth factor receptor 2) alterations and emerging NTRK (neurotrophic receptor tyrosine kinase) fusions and AXL-related pathways. Methods: A total of 48 patients with NSCLC was analyzed, including 22 women and 26 men (mean age 70 years, range 44–86). Tumor specimens were classified histologically as adenocarcinomas (n = 81%) or squamous cell carcinomas (n = 19%). Smoking history, PD-L1 (programmed death-ligand 1) expression, and genetic alterations were assessed. NGS (Next-generation sequencing) identified genomic variants, which were classified according to ACMG (American College of Medical Genetics and Genomics) guidelines. Results: The cohort consisted of 29 former smokers, 13 current smokers, and 5 non-smokers (12%), with a mean smoking burden of 33 pack years. PD-L1 TPS (tumor proportion score) was ≥50% in 10 patients, ≥1–<50% in 22, and <1% in 15 patients. In total, 120 genomic variants were detected (allele frequency ≥ 5%). Of these, 52 (43%) were classified as likely pathogenic or pathogenic, 48 (40%) as variants of unknown significance, and 20 (17%) as benign or likely benign. The most frequently altered genes were TP53 (tumor protein p53) (31%), KRAS and EGFR (15% each), and STK11 (serine/threonine kinase 11) (12%). Adenocarcinomas accounted for 89% of all alterations, with TP53 (21%) and KRAS (15%) being most common, while squamous cell carcinomas predominantly harbored TP53 (38%) and MET (15%) mutations. In patients with PD-L1 TPS ≥ 50%, KRAS mutations were enriched (50%), particularly KRAS G12C and G12D, with frequent co-occurrence of TP53 mutations (20%). No pathogenic EGFR mutations were detected in this subgroup. Conclusions: Comprehensive genomic profiling in NSCLC revealed a high prevalence of clinically relevant mutations, with TP53, KRAS and EGFR as the dominant drivers. The strong association of KRAS mutations with high PD-L1 expression, irrespective of smoking history, highlights the interplay between genetic and immunological pathways in NSCLC. These findings support the routine implementation of broad molecular testing to guide precision oncology approaches in both adenocarcinoma and squamous cell carcinoma patients. Full article

(This article belongs to the Section Cancer Pathophysiology)

15 pages, 4610 KB

Open AccessArticle

Cancer-Associated Fibroblast Heterogeneity Shapes Prognosis and Immune Landscapes in Head and Neck Squamous Cell Carcinoma

by Hideyuki Takahashi, Hiroyuki Hagiwara, Hiroe Tada, Miho Uchida, Toshiyuki Matsuyama and Kazuaki Chikamatsu

Cancers 2026, 18(2), 215; https://doi.org/10.3390/cancers18020215 - 9 Jan 2026

Abstract

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is a biologically heterogeneous malignancy with poor outcomes in advanced disease. Increasing evidence indicates that the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), plays an important role in tumor progression and immune regulation. However, the [...] Read more.

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is a biologically heterogeneous malignancy with poor outcomes in advanced disease. Increasing evidence indicates that the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), plays an important role in tumor progression and immune regulation. However, the diversity of CAF subsets and their clinical relevance in HNSCC remain incompletely understood. This study aimed to characterize CAF heterogeneity and assess the prognostic significance of CAF subset-specific transcriptional programs. Methods: Single-cell RNA sequencing data from HNSCC tumors were analyzed to identify CAF subsets based on differentially expressed genes. CAF subset-specific gene signatures were used to construct prognostic risk models for overall survival (OS) and progression-free survival (PFS) in The Cancer Genome Atlas HNSCC cohort, with validation in an independent dataset. CAF-driven prognostic groups were defined, and their immune landscapes and biological pathways were evaluated. Bulk RNA sequencing of primary CAF cultures was performed for validation. Results: Six CAF subsets were identified, including myofibroblastic (myCAF), inflammatory (iCAF), antigen-presenting, and extracellular matrix-related CAFs. Risk scores derived from inflammatory CAF subsets consistently predicted shorter OS across independent cohorts, whereas PFS prediction showed greater cohort dependency. CAF-based stratification identified patient subgroups with distinct immune profiles and pathway enrichment patterns. These results were supported by validation analyses and by bulk RNA sequencing of primary CAFs, demonstrating preservation of myCAF- and iCAF-like transcriptional programs ex vivo. Conclusions: CAF heterogeneity has important prognostic and immunological implications in HNSCC. Inflammatory CAF-related transcriptional programs represent robust markers of patient survival and may complement tumor-intrinsic biomarkers. Full article

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

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20 pages, 2290 KB

Open AccessArticle

Multi-Platform Detection of MMP-7 in Colorectal Carcinoma

by Ivana Večurkovská, Marek Stupák, Jana Kaťuchová, Veronika Roškovičová, Martin Pavluš, Mária Mareková and Jana Mašlanková

Cancers 2026, 18(2), 214; https://doi.org/10.3390/cancers18020214 - 9 Jan 2026

Abstract

Background/Objectives: Matrix metalloproteinase-7 (MMP-7) has been implicated in colorectal cancer (CRC) progression; however, its relationship to disease stage and its suitability as a circulating biomarker remain unclear. This study aimed to determine whether MMP-7 expression and activity differ between benign and malignant colorectal [...] Read more.

Background/Objectives: Matrix metalloproteinase-7 (MMP-7) has been implicated in colorectal cancer (CRC) progression; however, its relationship to disease stage and its suitability as a circulating biomarker remain unclear. This study aimed to determine whether MMP-7 expression and activity differ between benign and malignant colorectal conditions and whether serum MMP-7 levels reflect disease progression. Methods: mRNA MMP-7 expression data and MMP-7 levels have been collected from Gepia, Protein Atlas and UALCAN databases. For the study of patient samples, ELISA, Western blot, and zymography were used. The study included 30 patients with benign findings and 60 patients with colorectal cancer. The Gepia database reported significantly higher MMP-7 levels in patients with CRC. Results: The Protein Atlas and UALCAN highlight a notable difference between benign and malignant colon adenocarcinoma patients. The MMP-7 level in tissue samples from the malignant group, evaluated by Western blot, was approximately 4.5 times higher than in the benign group, and almost 3 times higher in serum samples. Using zymography, patients in the malignant group had MMP-7 activity more than 4x higher than that of patients in the benign group. The ELISA results supported this increase in MMP-7 levels. The average MMP-7 level in the malignant group was 1.2-fold that in benign tissue samples and approximately 3-fold that in serum samples. Notably, significant sex-related differences in serum MMP-7 concentrations were observed, indicating that gender may influence the interpretation of this biomarker. Conclusions: The discordance between stable MMP7 mRNA expression and declining serum MMP-7 protein levels in advanced CRC suggests complex post-transcriptional and post-translational regulation of MMP-7 during disease progression. Although this finding contrasts with much of the existing literature, it should be regarded as novel and hypothesis-generating. These results indicate that serum MMP-7 may reflect early tumor-associated processes rather than late-stage tumor burden, warranting further investigation in larger, stage-stratified and longitudinal cohorts. Full article

(This article belongs to the Section Clinical Research of Cancer)

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14 pages, 932 KB

Open AccessArticle

Impact of Neoadjuvant Induction Chemotherapy Prior to Chemoradiation on Survival and Surgical Outcomes in Real-World Esophageal Adenocarcinoma Cohort

by Thomas M. Matoska, Abdullah A. Memon, Lou-Anne Acevedo Moreno, Calista Bulacan, Lisa Rein, Anjishnu Banerjee, Ben George, Lauren Jurkowski, Alexandria Phan, Candice Johnstone, Monica E. Shukla, Elizabeth M. Gore, Paul Linsky, Mario Gasparri, Mallory Hunt and Lindsay L. Puckett

Cancers 2026, 18(2), 213; https://doi.org/10.3390/cancers18020213 - 9 Jan 2026

Abstract

Background/objectives: Improvements in esophageal adenocarcinoma (EAC) treatment have reduced mortality. While chemoradiation before surgery was previously a standard of care, updated guidelines recommend peri-operative chemotherapy without chemoradiation. Continued investigation into optimal non-operative treatment paradigms for patients who defer surgery or are not candidates [...] Read more.

Background/objectives: Improvements in esophageal adenocarcinoma (EAC) treatment have reduced mortality. While chemoradiation before surgery was previously a standard of care, updated guidelines recommend peri-operative chemotherapy without chemoradiation. Continued investigation into optimal non-operative treatment paradigms for patients who defer surgery or are not candidates for surgery and certain chemotherapy regimens is needed. The impact of induction chemotherapy prior to chemoradiation on survival and surgical outcomes remains unclear. This study assessed survival and surgical outcomes in a real-world cohort of EAC patients receiving induction chemotherapy before chemoradiation. Methods: This single-institution, IRB-approved, retrospective cohort study included patients with newly diagnosed stage II-IVb (oligometastatic for IVb) EAC who received definitive chemoradiation (radiation ≥ 40 Gy and two cycles of chemotherapy) +/− esophagectomy from 2007 to 2022. Patients receiving induction chemotherapy were compared to those who did not. Endpoints included survival and surgical outcomes. Results: A total of 141 EAC patients received definitive chemoradiation; 83 received induction chemotherapy before chemoradiation. Patients receiving induction chemotherapy were younger (p < 0.01) with slightly lower performance status (p = 0.27) and presented at a more advanced stage (p < 0.001). Median OS was 3.5 years in the induction chemotherapy group compared to 2.2 years (p = 0.10). There was no difference in pathologic complete response (p = 0.81), esophagectomy frequency (p = 0.87), or surgical downstaging between treatment groups (p = 0.84). Conclusions: In this real-world, single-institutional patient cohort investigating induction chemotherapy prior to chemoradiation in EAC, patients receiving induction chemotherapy did well but did not have a statistically significant improvement in survival outcomes or surgical outcomes. This study showed that significant numbers of real-world patients may not receive esophagectomy. Thus, prospective, randomized clinical trials are warranted to better delineate the efficacy and selection of patients for induction chemotherapy when non-operative approaches are favored. Full article

(This article belongs to the Special Issue Neoadjuvant Chemoradiotherapy for Gastrointestinal Cancer)

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19 pages, 2708 KB

Open AccessReview

A Comprehensive Review of Immunotherapeutic Modalities in Glioblastoma: Mechanisms, Efficacy, and Safety Considerations ^†

by Savi Agarwal, Simon Han, Aadi Lal, Viranshi Vira, Anubhav Chandla, Pasha Mehranpour, Isaac Yang and Madhuri Wadehra

Cancers 2026, 18(2), 212; https://doi.org/10.3390/cancers18020212 - 9 Jan 2026

Abstract

Background: Glioblastoma multiforme (GBM), the most aggressive primary brain malignancy in adults, is associated with poor prognosis and recurrence despite standard of care and newer immunotherapies. This warrants exploration of synergistic approaches such as combination immunotherapy for improved tumor control. Methods: We initiated [...] Read more.

Background: Glioblastoma multiforme (GBM), the most aggressive primary brain malignancy in adults, is associated with poor prognosis and recurrence despite standard of care and newer immunotherapies. This warrants exploration of synergistic approaches such as combination immunotherapy for improved tumor control. Methods: We initiated a systematic review of articles from 2015–2025 in PubMed, Embase, Scopus, Cochrane, and Web of Science if they assessed immunotherapy for GBM. Results: We included 49 studies (n = 3002 patients) with no significant demographic differences across publications. Combination immunotherapy regimens demonstrated higher pooled ORRs in limited comparative analyses, though findings were driven by a small number of studies. Single-arm analysis for overall survival (OS), progression-free survival (PFS), treatment-related adverse events (TRAEs), and ORR showed no significant differences among the groups. However, treatment–control arm analysis showed pooled ORs of 9.51 for combination immunotherapies and 0.44 in the control group. Conclusions: Combining immunotherapeutics across mechanisms may potentiate immune response effectiveness against GBM. Full article

(This article belongs to the Section Cancer Therapy)

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27 pages, 2824 KB

Open AccessArticle

Exploring the Impact of DNA Methylation on Gene Expression in CRC: A Computational Approach for Identifying Epigenetically Regulated Genes in Multi-Omic Datasets

by Andrei Stefan Blindu, Silvia Berardelli, Federica De Paoli, Federico Manai, Rossella Tricarico, Susanna Zucca and Paolo Magni

Cancers 2026, 18(2), 211; https://doi.org/10.3390/cancers18020211 - 9 Jan 2026

Abstract

Background/Objectives: DNA methylation is a key epigenetic process that regulates gene expression and is often disrupted in colorectal cancer (CRC). Aberrant methylation of promoter CpG islands can silence tumor suppressor genes and drive tumorigenesis. A subset of CRCs exhibits the CpG Island Methylator [...] Read more.

Background/Objectives: DNA methylation is a key epigenetic process that regulates gene expression and is often disrupted in colorectal cancer (CRC). Aberrant methylation of promoter CpG islands can silence tumor suppressor genes and drive tumorigenesis. A subset of CRCs exhibits the CpG Island Methylator Phenotype (CIMP), characterized by widespread hypermethylation and distinct clinical outcomes. Identifying genes whose expression is epigenetically regulated by methylation is important for prioritizing candidate biomarkers and therapeutic targets in CRC. Methods: We developed and compared a series of computational approaches to identify genes whose expression is regulated by DNA methylation in The Cancer Genome Atlas (TCGA) cohort of Colon Adenocarcinoma (COAD) patients. Samples were stratified according to their CpG Island Methylator Phenotype (CIMP) level to capture distinct epigenetic subgroups. The proposed framework integrates methylation and transcriptomic data to systematically detect methylation–expression associations indicative of epigenetic regulation. Results: The best-performing method identified gene sets strongly associated with promoter methylation–expression relationships and enriched for pathways relevant to colorectal cancer progression and patient stratification. To evaluate the robustness and transferability of the approach, it was further validated on independent datasets, including Stomach Adenocarcinoma (STAD), Glioblastoma Multiforme (GBM), and Mesothelioma (MESO), supporting its robustness and potential generalizability across multiple tumor types. Conclusions: Our study highlights the potential of computational pipelines to uncover epigenetically regulated genes in colorectal cancer. The identified candidate genes provide a hypothesis-generating foundation for refining molecular stratification and guiding future studies aimed at epigenetic biomarker discovery and therapeutic hypothesis development. Full article

(This article belongs to the Special Issue Novel Computational Approaches for Molecular Target Discovery in Colorectal Cancer)

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19 pages, 4339 KB

Open AccessArticle

Robust Multimodal Deep Learning for Lymphoma Subtype Classification Using ¹⁸F-FDG PET Maximum Intensity Projection Images and Clinical Data: A Multi-Center Study

by Seonhwa Kim, Jun Hyeong Park, Chul-Ho Kim, Seulgi You, Jeong-Seok Choi, Jae Won Chang, In Young Jo, Byung-Joo Lee, Il-Seok Park, Han Su Kim, Yong-Jin Park and Jaesung Heo

Cancers 2026, 18(2), 210; https://doi.org/10.3390/cancers18020210 - 9 Jan 2026

Abstract

Background: Previous attempts to classify lymphoma subtypes based on metabolic features extracted from ¹⁸F-FDG PET imaging have been hindered by inconsistencies in imaging protocols, scanner types, and inter-institutional variability. To overcome these limitations, we propose a multimodal deep learning framework that integrates [...] Read more.

Background: Previous attempts to classify lymphoma subtypes based on metabolic features extracted from ¹⁸F-FDG PET imaging have been hindered by inconsistencies in imaging protocols, scanner types, and inter-institutional variability. To overcome these limitations, we propose a multimodal deep learning framework that integrates harmonized PET imaging features with structured clinical information. The proposed framework is designed to perform hierarchical classification of clinically meaningful lymphoma subtypes through two sequential binary classification tasks. Methods: We collected multi-center data comprising ¹⁸F-FDG PET images and structured clinical variables of patients with lymphoma. To mitigate domain shifts caused by different scanner manufacturers, we integrated a Scanner-Conditioned Normalization (SCN) module, which adaptively harmonizes feature distributions using manufacturer-specific parameters. Performance was validated using internal and external cohorts, with the statistical significance of performance gains assessed via DeLong’s test and bootstrap-based CI analysis. Results: The proposed model achieved an area under the curve (AUC) of 0.89 (internal) and 0.84 (external) for Hodgkin lymphoma versus non-Hodgkin lymphoma classification and 0.84 (internal) and 0.76 (external) for diffuse large B-cell lymphoma versus follicular lymphoma classification (p > 0.05). These results were obtained using a multimodal model that integrated anterior and lateral maximum intensity projection (MIP) images with clinical data. Conclusions: This study demonstrates the potential of a deep learning-based approach for lymphoma subtype classification using non-invasive ¹⁸F-FDG PET imaging combined with clinical data. While further validation in larger, more diverse cohorts is necessary to address the challenges of rare subtypes and biological heterogeneity, LymphoMAP serves as a meaningful step toward developing assistive tools for early clinical decision-making. These findings underscore the feasibility of using automated pipelines to support, rather than replace, conventional diagnostic workflows in personalized lymphoma management. Full article

(This article belongs to the Section Cancer Pathophysiology)

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23 pages, 575 KB

Open AccessReview

A Bird’s Eye View: A Close Look into Avian CAM Models for Translational Blood Cancer Research

by Izabela M. Cymer, Niamh McAuley, Cathy E. Richards, Hanne Jahns, Siobhan V. Glavey and Ann M. Hopkins

Cancers 2026, 18(2), 209; https://doi.org/10.3390/cancers18020209 - 9 Jan 2026

Abstract

The chorioallantoic membrane (CAM) is a well-vascularised extra-embryonic membrane that supports avian embryonic development and can be used as an implantation site for xenograft models of various cancers. CAM tumour research models are powerful and versatile, offering a rapid, cost-effective and ethical complement [...] Read more.

The chorioallantoic membrane (CAM) is a well-vascularised extra-embryonic membrane that supports avian embryonic development and can be used as an implantation site for xenograft models of various cancers. CAM tumour research models are powerful and versatile, offering a rapid, cost-effective and ethical complement to mouse xenograft studies. Their capacity for real-time observation of tumour growth, angiogenesis and metastasis within an immunocompetent living organism is particularly compelling. While CAM models have been extensively utilised for investigating solid cancers, such as breast, lung and pancreatic, their potential for haematological malignancy research remains comparatively underexplored. This review examines the relevance, advantages and translational potential of avian CAM models in studying blood cancers. Their applications across three primary categories are discussed—leukaemias, lymphomas and myelomas—highlighting experimental approaches that replicate aspects of human disease progression and therapeutic responsiveness. Moreover, the review evaluates species-specific considerations relevant to model fidelity, including evolutionary distance and functional parallels between avian and human haematopoiesis. These comparisons underscore both the opportunities and limitations for utilising CAM models in haematologic malignancy research. For their potential to investigate mechanisms of cancer development and treatment in simple but immunocompetent in vivo settings, we propose that CAM tumour models offer high value as a bridge between in vitro and mammalian in vivo studies for haematology translational research. Full article

(This article belongs to the Special Issue Hematological Malignancies: From Translational Discoveries to Clinical Trends)

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12 pages, 247 KB

Open AccessArticle

Incidence and Characteristics of Perianal Infections in CPX-351-Treated AML Patients

by Elisa Buzzatti, Cristina Mauro, Cristiano Tesei, Giovangiacinto Paterno, Raffaele Palmieri, Fabiana Esposito, Elisa Meddi, Federico Moretti, Marco Zomparelli, Lucia Cardillo, Carmelo Gurnari, Luca Maurillo, Francesco Buccisano, Adriano Venditti and Maria Ilaria Del Principe

Cancers 2026, 18(2), 208; https://doi.org/10.3390/cancers18020208 - 9 Jan 2026

Abstract

Background: Perianal infections (PIs) are a serious threat in patients with acute myeloid leukemia (AML). While CPX-351 is designed to reduce gastrointestinal toxicity, its impact on the incidence of PIs is unknown. This study aims to evaluate the incidence and characteristics of PIs [...] Read more.

Background: Perianal infections (PIs) are a serious threat in patients with acute myeloid leukemia (AML). While CPX-351 is designed to reduce gastrointestinal toxicity, its impact on the incidence of PIs is unknown. This study aims to evaluate the incidence and characteristics of PIs in a cohort of CPX-351-treated AML patients. Methods: We enrolled 22 adult patients diagnosed with secondary AML receiving CPX-351 between May 2020 and July 2025 at Policlinico Tor Vergata Hospital. Statistical analysis used descriptive statistics and multivariate analysis. Results: The incidence of PIs in the cohort was 31.8%. Microbiological cultures from the lesions commonly yielded Klebsiella pneumoniae and Enterococcus species. The development of a PI was associated with a significantly longer hospital stay (mean, 49.6 vs. 37.7 days; p = 0.034). An increased odds ratio of having PIs was noted for mucositis and positive rectal swabs (17.961, p = 0.062; 5.554, p = 0.391, respectively), with two patients (28.5%) having a positive pre-infection swab for Klebsiella pneumoniae. Surgical intervention was guided by patient pain levels and hematological criteria. Surgical patients had significantly higher pain levels (p = 0.001) and a platelet count greater than 20 × 10⁹/L (p = 0.028). All patients were alive at 30 days, with low rates of septic shock (14.2%, n = 1) and no infection-related mortality or recurrence. Conclusions: Despite CPX-351’s known reduced gastrointestinal toxicity, our study showed a significantly higher incidence of PIs compared to literature data. While the outcomes were favorable, PIs led to prolonged hospitalization. Routine rectal swab surveillance could be a valuable tool for risk stratification and preemptive strategies. Full article

(This article belongs to the Special Issue The Unseen Burden: Incidence and Outcomes of Infections in Leukemia)

29 pages, 4039 KB

Open AccessReview

Targeting Mesenchymal-Epidermal Transition (MET) Aberrations in Non-Small Cell Lung Cancer: Current Challenges and Therapeutic Advances

by Fahua Deng, Weijie Ma and Sixi Wei

Cancers 2026, 18(2), 207; https://doi.org/10.3390/cancers18020207 - 8 Jan 2026

Abstract

The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, [...] Read more.

The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, including lung, breast, colorectal, and gastrointestinal cancers. In non–small cell lung cancer (NSCLC), aberrant activation of the MET proto-oncogene contributes to 1% of known oncogenic drivers and is associated with poor clinical outcomes. Several mechanisms can induce MET hyperactivation, including MET gene amplification, transcriptional upregulation of MET or HGF, MET fusion genes, and MET exon 14 skipping mutations. Furthermore, MET pathway activation represents a frequent mechanism of acquired resistance to EGFR- and ALK-targeted tyrosine kinase inhibitors (TKIs) in EGFR- and ALK-driven NSCLCs. Although MET has long been recognized as a promising therapeutic target in NSCLC, the clinical efficacy of MET-targeted therapies has historically lagged behind that of EGFR and ALK inhibitors. Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. They have also demonstrated potential in overcoming MET-driven resistance to EGFR TKIs or ALK TKIs. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC. Full article

(This article belongs to the Special Issue Advances in Precision Medicine: Targeting Known and Emerging Oncogenic Targets in Lung Cancer (2nd Edition))

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22 pages, 1518 KB

Open AccessReview

Adipokine Metabolic Drivers, Gut Dysbiosis, and the Prostate Microbiome: Novel Pathway Enrichment Analysis of the Adiposity-Based Chronic Disease—Prostate Cancer Network

by Zachary Dovey, Elena Tomas Bort and Jeffrey I. Mechanick

Cancers 2026, 18(2), 206; https://doi.org/10.3390/cancers18020206 - 8 Jan 2026

Abstract

Adiposity-Based Chronic Disease (ABCD) is known to increase the risk of aggressive prostate cancer (PCa), recurrent disease after treatment for localized PCa, and PCa mortality. A key mechanistic link contributing to this enhanced risk is chronic inflammation originating from excess white visceral adipose [...] Read more.

Adiposity-Based Chronic Disease (ABCD) is known to increase the risk of aggressive prostate cancer (PCa), recurrent disease after treatment for localized PCa, and PCa mortality. A key mechanistic link contributing to this enhanced risk is chronic inflammation originating from excess white visceral adipose tissue (WAT; VAT) and periprostatic adipose tissue (ppWAT). Contributing to systemic inflammation is gut dysbiosis, which itself may be caused by ABCD as well as background local inflammation (prostatitis), which is common in aging men and may be exacerbated by the urinary microbiome. Investigating the molecular biology driving inflammation and its association with increased PCa risk, a recent paper applied a network and gene set enrichment to adipokine drivers in the ABCD-PCa network. It found prominent roles for MCP-1, IL-1β, and CXCL-1 in addition to confirming the importance of exposure to lipopolysaccharides and bacterial components, corroborating the role of gut dysbiosis. To further unravel the mechanistic links between ABCD and PCa risk, this critical review will discuss the current literature on prominent inflammatory signaling pathways activated in ABCD; the influence of gut dysbiosis, the urinary microbiome, and chronic prostatitis; and current hypotheses on how these domains may result in the development of aggressive PCa over a man’s life. Moreover, we performed a novel pathway enrichment analysis to further evaluate the associations between ABCD, PCa risk, gut dysbiosis, and the prostate microbiome, the results of which were partitioned into extracellular and intracellular signaling pathways. In the extracellular space, novel mechanistic links between gut dysbiosis and MCP-1, IL-1β, CXCL1, and leptin via bacterial pathogen signaling and the intestinal immune network (for IgA production), crucial for gut immune homeostasis, were found. Within the intracellular space, there were downstream signals activating chemokine and type 2 interferon pathways, focal adhesion PI3K/Akt/mTOR pathways, as well as the JAK/STAT, NF-κB, and PI3K/Akt pathways. Overall, these findings point to an emerging molecular pathway for PCa oncogenesis influenced by ABCD, gut dysbiosis, and inflammation, and further research, possibly with lifestyle program-based clinical trials, may discover novel biomarker panels and molecular targeted therapies for the prevention and treatment of PCa. Full article

(This article belongs to the Special Issue Advances in the Diagnosis and Treatment of Prostate Cancer: From Biomarkers to Precision Surgery)

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15 pages, 1216 KB

Open AccessReview

Autophagy Modulates Immunogenic Cell Death in Cancer

by Maiko Matsushita and Miyu Moriwaki

Cancers 2026, 18(2), 205; https://doi.org/10.3390/cancers18020205 - 8 Jan 2026

Abstract

Immunogenic cell death (ICD) is a subtype of regulated cell death characterized by the spatiotemporally coordinated emission of damage-associated molecular patterns (DAMPs), such as calreticulin (CALR), ATP, and high-mobility group box-1 (HMGB1), which collectively prime tumor-specific T-cell responses. Autophagy, a lysosome-dependent catabolic process, [...] Read more.

Immunogenic cell death (ICD) is a subtype of regulated cell death characterized by the spatiotemporally coordinated emission of damage-associated molecular patterns (DAMPs), such as calreticulin (CALR), ATP, and high-mobility group box-1 (HMGB1), which collectively prime tumor-specific T-cell responses. Autophagy, a lysosome-dependent catabolic process, is increasingly recognized as a key modifier of antitumor immunity and the tumor microenvironment (TME). In preclinical models, autophagy can not only promote ICD by sustaining endoplasmic reticulum (ER) stress, eukaryotic translation initiation factor-2α (eIF2α) phosphorylation, and secretory pathways, but it can also limit ICD by degrading DAMPs, antigenic cargo, and major histocompatibility complex (MHC) molecules. The net outcome is highly context-dependent and determined by the tumor type, the nature and intensity of the stress, and the level at which autophagy is modulated. Herein, we summarize how autophagy affects the three canonical ICD-associated DAMPs, highlight solid-tumor models in which autophagy supports ICD, and contrast them with systems wherein autophagy inhibition is required for immunogenicity. We then focus on hematological malignancies, especially multiple myeloma, where recent reports implicate the autophagy-related protein GABARAP in bortezomib-induced ICD. Finally, we discuss the translational implications, including rational combinations of autophagy modulators with ICD-inducing chemotherapies, targeted drugs, and cellular immunotherapies, and outline the remaining challenges for safely harnessing the autophagy–ICD axis in the clinical setting. Full article

(This article belongs to the Special Issue Autophagy and Apoptosis in Cancer Progression)

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2 pages, 888 KB

Open AccessCorrection

Correction: Kingshott et al. Alteration of Metabolic Conditions Impacts the Regulation of IGF-II/H19 Imprinting Status in Prostate Cancer. Cancers 2021, 13, 825

by Georgina Kingshott, Kalina Biernacka, Alex Sewell, Paida Gwiti, Rachel Barker, Hanna Zielinska, Amanda Gilkes, Kathryn McCarthy, Richard M. Martin, J. Athene Lane, Lucy McGeagh, Anthony Koupparis, Edward Rowe, Jon Oxley, Jeff M. P. Holly and Claire M. Perks

Cancers 2026, 18(2), 204; https://doi.org/10.3390/cancers18020204 - 8 Jan 2026

Abstract

In the original publication [...] Full article

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27 pages, 759 KB

Open AccessReview

Dietary Fiber and Melanoma: Exploring Microbiome-Driven Immune Modulation

by Laci Turner, Connor K. Sisk and Nabiha Yusuf

Cancers 2026, 18(2), 203; https://doi.org/10.3390/cancers18020203 - 8 Jan 2026

Abstract

Background/Objectives: The gut microbiome influences melanoma biology and response to immune checkpoint inhibitors. Dietary fiber is a key modifiable factor that shapes the microbial composition and metabolite production. This review summarizes mechanistic, preclinical, and clinical evidence describing how fiber and fiber-responsive taxa [...] Read more.

Background/Objectives: The gut microbiome influences melanoma biology and response to immune checkpoint inhibitors. Dietary fiber is a key modifiable factor that shapes the microbial composition and metabolite production. This review summarizes mechanistic, preclinical, and clinical evidence describing how fiber and fiber-responsive taxa may affect melanoma immunity and treatment outcomes. Methods: A literature search of MEDLINE, Embase, and Scopus identified studies published within the past five years examining dietary fiber, gut microbiome interactions, immune modulation, or melanoma outcomes. After screening 491 unique records, 49 peer-reviewed mechanistic, preclinical, observational, and interventional studies were synthesized qualitatively in this narrative review. Results: Fiber fermentation produces short-chain fatty acids that regulate dendritic cell activation, T-cell priming, and cytokine signaling. Preclinical melanoma models show that fibers such as inulin and β-glucan enhance IFN-γ-driven antitumor immunity, increase CD8⁺ infiltration, and improve checkpoint blockade efficacy in a microbiota-dependent manner. In humans, fiber-rich diets and enrichment of taxa such as Bifidobacterium, Faecalibacterium, and Akkermansia are associated with improved PD-1 inhibitor responses, longer progression-free survival, and possible reductions in ICI-related colitis. Although epidemiologic studies suggest no clear association between fiber intake and melanoma incidence, dietary fiber intake appears to correlate strongly with treatment-related outcomes. Conclusions: Dietary fiber represents a potentially safe and plausible adjunct to melanoma immunotherapy. However, study variability and emerging counterevidence highlight the need for controlled trials to clarify causality and define optimal fiber-based interventions. Full article

(This article belongs to the Special Issue Gut Microbiome, Diet and Cancer Risk)

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2 pages, 174 KB

Open AccessCorrection

Correction: Rizzo et al. Endoscopic Ultrasound-Guided Anastomoses of the Gastrointestinal Tract: A Multicentric Experience. Cancers 2025, 17, 910

by Giacomo Emanuele Maria Rizzo, Chiara Coluccio, Edoardo Forti, Alessandro Fugazza, Cecilia Binda, Giuseppe Vanella, Francesco Maria Di Matteo, Stefano Francesco Crinò, Andrea Lisotti, Marcello Fabio Maida, Giovanni Aragona, Aurelio Mauro, Alessandro Repici, Andrea Anderloni, Carlo Fabbri, Ilaria Tarantino and on behalf of the I-EUS Group

Cancers 2026, 18(2), 202; https://doi.org/10.3390/cancers18020202 - 8 Jan 2026

Abstract

In the published publication [...] Full article

(This article belongs to the Special Issue Gastrointestinal and Its Associated Malignancies: Diagnosis, Targets and Therapies)

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