Cancers

16 pages, 1931 KB

Open AccessArticle

Nationwide Trends and Projections of Early Onset Gastrointestinal Cancers in China

by Tianyu Li, Chen Lin and Weibin Wang

Cancers 2025, 17(18), 2954; https://doi.org/10.3390/cancers17182954 (registering DOI) - 9 Sep 2025

Early-onset (15–49 years) gastrointestinal cancers are an emerging public health concern in China, yet national trend analyses remain limited. Drawing on data from the Global Burden of Disease 2021 study, we evaluated nationwide trends in the incidence and mortality of early-onset gastrointestinal cancers [...] Read more.

Early-onset (15–49 years) gastrointestinal cancers are an emerging public health concern in China, yet national trend analyses remain limited. Drawing on data from the Global Burden of Disease 2021 study, we evaluated nationwide trends in the incidence and mortality of early-onset gastrointestinal cancers (esophagus, stomach, liver, colon and rectum, gallbladder and biliary tract, and pancreas) in China from 1990 to 2021 and projected future patterns through 2040 using Bayesian age–period–cohort models. Between 1990 and 2021, age-standardized rates for esophageal, stomach, and liver cancers declined markedly while those for colorectal and biliary tract cancers increased, and pancreatic cancer rates rose modestly. Mortality for upper-GI cancers fell substantially, whereas colorectal cancer deaths rose modestly, with the age-standardized mortality rate declining despite rising incidence. Projections suggest continued declines in upper-GI cancers, further increases in colorectal and biliary tract cancers, and a peak in the age-standardized incidence rate of pancreatic cancer around 2030. These divergent trends highlight an urgent need for targeted prevention and early-detection strategies focused on colorectal, biliary, and pancreatic cancers among patients aged 15–49 years in China. Full article

(This article belongs to the Special Issue Gastrointestinal Malignancy: Epidemiology and Risk Factors)

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29 pages, 3313 KB

Open AccessSystematic Review

Epigenetic Reprogramming by Decitabine in Triple-Negative Breast Cancer: Mechanisms, Immune Modulation, and Therapeutic Synergy

by Fathima Raahima Riyas Mohamed, Safiah Aldubaisi, Arshiya Akbar, Mohammad Imran Khan and Ahmed Yaqinuddin

Cancers 2025, 17(18), 2953; https://doi.org/10.3390/cancers17182953 (registering DOI) - 9 Sep 2025

Abstract

Background/Objectives: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking ER, PR, and HER2 expression, with limited targeted therapies and poor outcomes. Epigenetic dysregulation, particularly aberrant DNA methylation, is a key driver. Decitabine, a DNA methyltransferase inhibitor (DNMTi), shows promise by reactivating [...] Read more.

Background/Objectives: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking ER, PR, and HER2 expression, with limited targeted therapies and poor outcomes. Epigenetic dysregulation, particularly aberrant DNA methylation, is a key driver. Decitabine, a DNA methyltransferase inhibitor (DNMTi), shows promise by reactivating silenced tumor suppressor genes and modulating immune responses. This systematic review evaluates preclinical and clinical evidence on decitabine’s efficacy, mechanisms, and translational potential in TNBC. Methods: A PRISMA-2020 compliant search of PubMed, EBSCO, Web of Science, and Semantic Scholar was conducted up to April 2025. Included studies assessed decitabine alone or in combination in TNBC preclinical or clinical settings. Risk of bias was assessed using QUIPS and RoB 2.0 tools. Results: Twenty-five studies were included. In vitro, decitabine-induced growth inhibition, apoptosis, and re-expression of silenced genes (such as BRCA1 and CDH1). In vivo, it reduced tumor burden and enhanced anti-tumor immunity through MHC-I, PD-L1, and STING pathway upregulation. Synergy was noted with anti-PD-1, HDAC inhibitors, and chemotherapy. Resistance mechanisms included persistent DNMT activity, low DCK, and miRNA-driven escape (miR-155–TSPAN5). Conclusions: Decitabine demonstrates strong preclinical and early clinical potential in TNBC via epigenetic reprogramming and immune activation. Future strategies should focus on biomarker-based selection and resistance mitigation. Full article

(This article belongs to the Special Issue Epigenetics in Cancer and Drug Therapeutics)

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15 pages, 1432 KB

Open AccessArticle

Survival Machine Learning Methods Improve Prediction of Histologic Transformation in Follicular and Marginal Zone Lymphomas

by Tong-Yoon Kim, Tae-Jung Kim, Eun Ji Han, Gi-June Min, Seok-Goo Cho, Seoree Kim, Jong Hyuk Lee, Byung-Su Kim, Joon Won Jeoung, Hye Sung Won and Youngwoo Jeon

Cancers 2025, 17(18), 2952; https://doi.org/10.3390/cancers17182952 (registering DOI) - 9 Sep 2025

Abstract

Background/Objectives: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are low-grade B-cell lymphomas (LGBCLs) with indolent clinical courses but a lifelong risk of histologic transformation (HT) to aggressive lymphomas, particularly diffuse large B-cell lymphoma. Predicting HT can be challenging due to class imbalances [...] Read more.

Background/Objectives: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are low-grade B-cell lymphomas (LGBCLs) with indolent clinical courses but a lifelong risk of histologic transformation (HT) to aggressive lymphomas, particularly diffuse large B-cell lymphoma. Predicting HT can be challenging due to class imbalances and the inherent complexity of time-dependent events. While there are current prognostic indices for survival, they do not specifically address HT risk. This study aimed to develop and validate survival-based and traditional classification machine-learning models to predict HT in cohorts. Methods: Using a multicenter retrospective dataset (n = 1068), survival models (Cox proportional hazards, Lasso-Cox, Random Survival Forest, Gradient-boosted Cox [GBM-Cox], eXtreme Gradient Boosting [XGBoost]-Cox), and classification models (Logistic regression, Lasso logistic, Random Forest, Gradient Boosting, XGBoost) were compared. The best-performing survival models—XGBoost-Cox, Lasso-Cox, and GBM-Cox—were assessed on an independent test set (n = 92). Model sensitivity was maximized using optimal binary risk cutoff points based on Youden’s index. Results: Survival models showed superior predictive performance than classical classifiers, with XGBoost-Cox exhibiting the highest mean accuracy (85.3%), time-dependent area under the curve (0.795), sensitivity (98%), specificity (83.9%), and concordance index (0.836). Incorporating next-generation sequencing (NGS) data improved model accuracy and specificity, indicating that genetic factors improve HT prediction. Principal component analysis revealed distinct gene mutation patterns associated with HT risk, highlighting DNA-repair genes such as TP53, BLM, and RAD50. Conclusions: This study highlights the clinical value of survival-based machine-learning methods integrated with NGS data to personalize HT risk stratification for patients with FL and MZL. Full article

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

15 pages, 794 KB

Open AccessSystematic Review

Rehabilitation Protocols and Functional Outcomes in Oncological Patients Treated with Modular Megaprosthesis: A Systematic Review

by Filip Fryderyk Brzeszczyński, Michał Karpiński, Marcel Aleksander Brzeszczyński, Oktawiusz Bończak and David F. Hamilton

Cancers 2025, 17(18), 2951; https://doi.org/10.3390/cancers17182951 (registering DOI) - 9 Sep 2025

Abstract

Background/Objectives: Bone reconstruction using megaprostheses is increasingly performed following bone tumour resections, including sarcomas, to enhance patient outcomes and quality of life. However, this is a complex patient group, and there is little consensus as to postoperative rehabilitation and associated outcomes. Methods: A [...] Read more.

Background/Objectives: Bone reconstruction using megaprostheses is increasingly performed following bone tumour resections, including sarcomas, to enhance patient outcomes and quality of life. However, this is a complex patient group, and there is little consensus as to postoperative rehabilitation and associated outcomes. Methods: A systematic search was conducted in MEDLINE and EMBASE databases according to the Implementing Prisma in Exercise, Rehabilitation, Sport medicine and SporTs science (PERSiST) guidelines. Studies describing rehabilitation protocols and functional outcomes following bone tumour resection and modular oncologic megaprosthesis reconstruction were included. All papers were individually assessed for methodological quality using the Joanna Briggs Institute (JBI) critical appraisal tool. Results: The search generated 105 records, 28 underwent full-text review, and 13 studies were included. Available data reflect 371 patients with a mean age of 49.17 (S.D. 21.40) years and a mean postoperative follow-up of 41.88 (S.D. 32.88) months. Surgical indications were documented as sarcomas in 9 studies, and tumour metastasis to the bone in 10 studies. Rehabilitation protocols were reported in 5 studies following proximal humerus resection with a mean dislocation rate of 14.5% (S.D. 5.26). All protocols advised brace immobilisation for a period ranging between 10 days and 6 months. Superior Constant-Murley shoulder score was reported in patients with early active isometric exercises at 6 weeks. Six studies reported proximal femur prosthesis rehabilitation and functional outcomes, with a mean dislocation rate of 10% (S.D. 9.82). Enhanced outcomes were reported in studies employing early mobilisation. Two studies assessed distal femur prosthesis; both studies reported similar protocols with full weight bearing 3 weeks following surgery. The methodological quality of the studies varied, but was overall modest, with 10/13 studies meeting at least 50% of JBI reporting criteria. Conclusions: The existing literature on rehabilitation and outcomes in orthopaedic oncology patients following arthroplasty with megaprosthesis is limited, with rehabilitative protocols variably described. However, it seems that early active mobilisation does not increase the risk of joint dislocations or infections. Full article

(This article belongs to the Special Issue Sarcoma Management in Orthopaedic Oncology)

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16 pages, 3357 KB

Open AccessArticle

Cabozantinib Sensitizes NSCLC Cells to Radiation by Inducing Ferroptosis via STAT3/MCL1/BECN1/SLC7A11 Axis Suppression

by Cheng-Yi Wang, Chao-Yuan Huang, Li-Ju Chen, Grace Chen and Shiao-Ya Hong

Cancers 2025, 17(18), 2950; https://doi.org/10.3390/cancers17182950 (registering DOI) - 9 Sep 2025

Abstract

Background/Objectives: Intrinsic radioresistance in non-small-cell lung cancer (NSCLC) is partially driven by adaptive redox mechanisms that prevent oxidative cell death. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a potential therapeutic vulnerability in tumors with elevated [...] Read more.

Background/Objectives: Intrinsic radioresistance in non-small-cell lung cancer (NSCLC) is partially driven by adaptive redox mechanisms that prevent oxidative cell death. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a potential therapeutic vulnerability in tumors with elevated antioxidant capacity. However, its mechanistic integration with radiotherapy remains incompletely understood. Methods: We compared the effects of three clinically approved VEGFR-targeting tyrosine kinase inhibitors (TKIs), cabozantinib, lenvatinib, and ripretinib, on NSCLC cell viability with and without radiation. Subsequent mechanistic studies focused on cabozantinib and included ferroptosis rescue assays (ferrostatin-1, deferoxamine), lipid ROS quantification, glutathione assays, clonogenic survival, co-immunoprecipitation of BECN1–SLC7A11 complexes, and BECN1 knockdown by siRNA and shRNA. Results: All three TKIs were evaluated for cytotoxicity, but only cabozantinib significantly reduced NSCLC cell viability in combination with radiation in a ferroptosis-dependent manner. Cabozantinib inhibited STAT3 phosphorylation and downregulated MCL1, resulting in the release of BECN1. This allowed BECN1 to bind and suppress SLC7A11, disrupting system Xc⁻ function, depleting glutathione, and promoting lipid ROS accumulation. Genetic silencing of BECN1 reversed these effects and restored redox balance and clonogenic capacity. Lenvatinib and ripretinib failed to elicit similar responses, indicating that the inhibition of non-VEGFR targets (e.g., MET, AXL) may be essential for ferroptosis induction by cabozantinib. Conclusions: Cabozantinib enhances the radiosensitization of NSCLC cells through ferroptosis induction mediated by the suppression of the STAT3/MCL1/BECN1/SLC7A11 axis. These findings uncover a novel mechanism linking kinase inhibition to redox imbalance and suggest that the pharmacologic modulation of ferroptosis using multi-target TKIs may represent a rational approach to overcome radioresistance in NSCLC. Full article

(This article belongs to the Special Issue Advances in Lung Cancer Treatment Strategies)

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21 pages, 7246 KB

Open AccessArticle

Heterogeneity of Tertiary Lymphoid Structures and Plasma Cells in PDAC with and Without Lymph Node Metastasis

by Mengfei Wang, Lizhi Zhang and Hailong Chen

Cancers 2025, 17(18), 2949; https://doi.org/10.3390/cancers17182949 - 9 Sep 2025

Abstract

Background/Objectives: TLSs are favorable PDAC prognostic biomarkers. However, the mechanisms underlying TLSs formation and their contribution to the humoral antitumor immune response remain poorly understood. Methods: We used mIF staining combined with AI-based pathological image analysis software to assess the heterogeneity [...] Read more.

Background/Objectives: TLSs are favorable PDAC prognostic biomarkers. However, the mechanisms underlying TLSs formation and their contribution to the humoral antitumor immune response remain poorly understood. Methods: We used mIF staining combined with AI-based pathological image analysis software to assess the heterogeneity in the distribution of TLSs, B cells, plasma cells, and tumor cells between N0 and N1/2 PDAC. Three scRNA-seq datasets and the TCGA-PAAD database were utilized to investigate the functional heterogeneity in B cells and plasma cells. Results: The TLS area and maturity in N0 PDAC were higher than those in N1/2 PDAC. The densities of memory B cells and germinal-center B cells in intratumoral mTLSs, as well as plasma cells in stromal imTLSs, were associated with the density of intratumoral plasma cells. Moreover, plasma cells in N0 PDAC exhibited stronger IgG antibody production than those in N1/2 PDAC. IgG⁺ tumor cells congregated within 40 μm of IgG⁺ plasma cells, forming an IgG⁺ plasma cell-related immune hotspot in N0 PDAC, which was not observed in N1/2 PDAC. The distance between IgG⁺ plasma cells and the nearest IgG⁺ tumor cells was a new prognosis biomarker. Conclusions: The TLS formation and development in N0 PDAC were better than those in N1/2 PDAC, and there is an IgG⁺ plasma cell-related immune hotspot in N0 PDAC. The TLS area and maturity and the distance between IgG⁺ plasma cells and the nearest IgG⁺ tumor cells could be PDAC prognostic biomarkers. Full article

(This article belongs to the Section Tumor Microenvironment)

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Graphical abstract

20 pages, 1377 KB

Open AccessArticle

Dendritic Cells of Leukemic Origin (DC_leu) Modulate the Expression of Inhibitory Checkpoint Molecules and Their Ligands on T Cells and Blasts in AML Relapse After Allogeneic Stem Cell Transplantation

by Xiaojia Feng, Giuliano Filippini Velázquez, Sophia Bohlscheid, Marianne Unterfrauner, Philipp Anand, Hazal Aslan Rejeski, Anne Hartz, Tobias Baudrexler, Christoph Schmid and Helga Maria Schmetzer

Cancers 2025, 17(18), 2948; https://doi.org/10.3390/cancers17182948 - 9 Sep 2025

Abstract

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for high-risk acute myeloid leukemia and myelodysplastic neoplasms (AML/MDS). However, AML/MDS relapse post-transplant is driven by immune escape mechanisms, limiting treatment options and contributing to poor prognosis. Granulocyte–Macrophage Colony-Stimulating Factor (GM-CSF) [...] Read more.

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for high-risk acute myeloid leukemia and myelodysplastic neoplasms (AML/MDS). However, AML/MDS relapse post-transplant is driven by immune escape mechanisms, limiting treatment options and contributing to poor prognosis. Granulocyte–Macrophage Colony-Stimulating Factor (GM-CSF) and Prostaglandin-E1 (PGE-1) (termed “Kit M”) induce dendritic cells of leukemic origin (DC_leu) that have been shown to induce antileukemic immune responses. Methods: Using flow cytometry, we analyzed ICM/ICML-expressing uncultured T-cells/blasts in whole blood (WB) samples from patients with AML/MDS relapse post-allo-HCT who had received salvage treatment. Using Kit M, DC_leu were generated ex vivo. T-cell-enriched mixed-lymphocyte cultures (MLC) were performed for functional assessment of DC/DC_leu to stimulate (leukemia specifically) patients’ immune cells. After MLC, ICM/ICML-expressing cells and immune activation were assessed. The experimental results were correlated with patients’ clinical responses to salvage treatment. Results: WB samples from 15 patients were analyzed. On average, high frequencies of ICM (CTLA4/PD1)-co-expressing blasts and high frequencies of ICM (CTLA4/PD1/TIGIT/TIM3/2B4)-co-expressing T-cells were found in uncultured WB, compared to the frequencies of healthy ICM-expressing T-cells. Treatment with Kit M induced DC/DC_leu, which, after MLC, downregulated ICM-expressing T-cells and enhanced activated and memory T-cells. High frequencies of ICM-co-expressing uncultured T-cells/blasts correlated negatively with the blast lysis capacity and patients’ clinical response to relapse treatment. However, post-MLC, Kit-mediated modulation of ICM-expressing T cells did not correlate with blast lysis, nor with patients’ clinical response to treatment. Conclusions: We conclude that Kit M contributes to overcoming impaired antileukemic reactions, independent of the presence of ICM-expressing T-cells in relapsed AML patients after allo-HCT ex vivo. Full article

(This article belongs to the Special Issue The New Challenge of Curing AML: Analysis of Mechanisms of Resistance of Target Drugs and Future Perspectives)

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25 pages, 8719 KB

Open AccessArticle

Cell Line-Dependent Internalization, Persistence, and Immunomodulatory Effects of Staphylococcus aureus in Triple-Negative Breast Cancer

by Sima Kianpour Rad, Runhao Li, Kenny K. L. Yeo, Clare Cooksley, Gohar Shaghayegh, Sarah Vreugde, Fangmeinuo Wu, Yoko Tomita, Timothy J. Price, Wendy V. Ingman, Amanda R. Townsend and Eric Smith

Cancers 2025, 17(18), 2947; https://doi.org/10.3390/cancers17182947 - 9 Sep 2025

Abstract

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options and inconsistent response to immune checkpoint inhibitors (ICIs). Emerging evidence indicates that tumor-associated bacteria may shape immune signaling and alter immunotherapy outcomes. Here, we investigated whether Staphylococcus aureus invades TNBC [...] Read more.

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options and inconsistent response to immune checkpoint inhibitors (ICIs). Emerging evidence indicates that tumor-associated bacteria may shape immune signaling and alter immunotherapy outcomes. Here, we investigated whether Staphylococcus aureus invades TNBC cells, persists intracellularly, and modulates PD-L1 expression. Methods: Using eFluor450-labeled S. aureus for flow cytometry, gentamicin protection assays, CFU quantification, and transmission electron microscopy, we assessed bacterial uptake and persistence in six TNBC cell lines and a non-tumorigenic control. PD-L1, TLR2, and STAT1 activation were evaluated after infection or TLR2 ligand treatment ± IFN-γ. Results: At multiplicity of infection (MOI) of 10, S. aureus internalized into 67% of MDA-MB-468 and 54% of MDA-MB-231, with intermediate uptake in Hs578T (27%) and BT-549 (24%) and only 0.5–9% in low-uptake lines (MDA-MB-453, CAL-51, MCF-12A). High-uptake lines exhibited marked cytotoxicity and reduced proliferation, with MDA-MB-468 showing an 82% drop in viability at 2 h and a 74% decrease after 5 d, whereas low-uptake lines showed minimal impact. Persistence lasted >7 d in MDA-MB-231 but only 3–5 days in others. IFN-γ plus S. aureus significantly amplified PD-L1, with up to a 2.9-fold increase in MDA-MB-468 and 1.5-fold in MDA-MB-231, but no effect in low-uptake lines. TLR2 agonists modestly increased PD-L1 in high-TLR2-expressing lines and synergized with IFN-γ. These effects were accompanied by STAT1 phosphorylation, supporting a TLR2/STAT1 axis linking bacterial sensing to immune checkpoint regulation. Conclusions: Together, these findings identify S. aureus as a modulator of immune signaling in TNBC and highlight the potential for microbial factors to influence ICI responsiveness. Targeting tumor–bacteria interactions may represent a novel strategy to enhance immunotherapy efficacy in breast cancer. Full article

(This article belongs to the Special Issue New Insights into Microbial-Based Cancer Therapy)

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24 pages, 1888 KB

Open AccessReview

Influence of Genetic, Dietary, and Environmental Factors on Natural Killer (NK) Cell Biology and Function: Interplay Between NK Cell Activity and Cancer Onset or Progression

by Kawaljit Kaur

Cancers 2025, 17(18), 2946; https://doi.org/10.3390/cancers17182946 - 9 Sep 2025

Abstract

The connection between NK cells and cancer offers valuable insights into disease management. Suppressing NK cells can encourage cancer growth, while cancer itself can weaken NK cell function. This review examines how genetic and environmental factors such as diet affect NK cell numbers [...] Read more.

The connection between NK cells and cancer offers valuable insights into disease management. Suppressing NK cells can encourage cancer growth, while cancer itself can weaken NK cell function. This review examines how genetic and environmental factors such as diet affect NK cell numbers and function during the early stages of cancer. It also explores the reduced NK cell activity in cancer-bearing mouse models and human patients. The mechanisms behind cytotoxic actions and cytokine release are analyzed across four NK cell maturation stages. This understanding highlights the potential of using healthy donor NK cells for immunotherapy, alongside the role of memory NK cells in treatments. While NK cell-based therapies show promise in studies, challenges remain in sustaining their effectiveness and durability. This review also discusses strategies to improve production and boost the efficiency of donor NK cell therapies. Full article

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

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26 pages, 1535 KB

Open AccessReview

Harnessing p97/VCP: A Transformative AAA+ ATPase Target for Next-Generation Cancer Therapeutics

by Maria Janina Carrera Espinoza, Sarah K. Tucker, Sruthi Sureshkumar, Madison E. Gamble, Natalie L. Hakim, Sofia Orrantia, Claudia M. Espitia, Alexis B. Cruickshank-Taylor, Wei Wang, Kevin R. Kelly, Jennifer S. Carew and Steffan T. Nawrocki

Cancers 2025, 17(18), 2945; https://doi.org/10.3390/cancers17182945 - 9 Sep 2025

Abstract

Increased basal protein synthesis activity is a hallmark feature that distinguishes many types of malignant cells from their normal counterparts. The survival and proliferation of cancer cells are tightly linked to functional unfolded protein response (UPR) and endoplasmic reticulum (ER)-associated degradation (ERAD) pathways [...] Read more.

Increased basal protein synthesis activity is a hallmark feature that distinguishes many types of malignant cells from their normal counterparts. The survival and proliferation of cancer cells are tightly linked to functional unfolded protein response (UPR) and endoplasmic reticulum (ER)-associated degradation (ERAD) pathways due to their high rates of protein synthesis. The evolutionarily conserved AAA+ ATPase valosin-containing protein (VCP)/p97 facilitates the extraction of proteins from organelles, chromatin, and protein complexes to target them for ubiquitin–proteasome system (UPS)-mediated degradation. p97 plays a key role in protein quality control and in the maintenance of protein homeostasis through its regulation of ERAD. The disruption of p97 activity leads to an accumulation of undegraded proteins, triggers the UPR, and can culminate in proteotoxic cell death. Given this, p97 inhibition offers an opportunity to selectively kill cancer cells that exhibit high basal protein synthesis rates. This review explores p97’s molecular structure, diverse cellular roles, and clinical potential with a particular focus on CB-5083 and CB-5339, the only p97 inhibitors to date that have advanced into clinical trials. We discuss their mechanisms of action, clinical trial outcomes, and the transformative potential of rational combination strategies to maximize their therapeutic potential. By integrating foundational biological insights with translational perspectives, we highlight p97 as a precision target for cancer treatment. Full article

(This article belongs to the Special Issue Next-Generation Cancer Therapies)

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15 pages, 2172 KB

Open AccessCommunication

Triangulating Timing, Tropism and Burden of Sarcoma Metastases: Toward Precision Surveillance and Therapy in a Real-World-Time Cohort

by Philip Heesen, Dario Feusi, Bettina Vogel, Gabriela Studer, Bruno Fuchs and on behalf of the Swiss Sarcoma Network

Cancers 2025, 17(18), 2944; https://doi.org/10.3390/cancers17182944 - 9 Sep 2025

Abstract

Background: Sarcoma surveillance guidelines still apply uniform imaging intervals based on tumor grade and stage that ignore histotype-specific metastatic behavior. We prospectively analyzed metastatic timing, organ tropism, and lesion burden across a real-world sarcoma cohort to generate an evidence base for risk-adapted [...] Read more.

Background: Sarcoma surveillance guidelines still apply uniform imaging intervals based on tumor grade and stage that ignore histotype-specific metastatic behavior. We prospectively analyzed metastatic timing, organ tropism, and lesion burden across a real-world sarcoma cohort to generate an evidence base for risk-adapted follow-up and treatment stratification. Methods: In a prospective multicenter study, 1850 patients with suspected sarcoma were screened. SHAPEHub, a real-world-time data warehouse, captured clinicopathological variables and imaging. Adults with histologically confirmed soft-tissue or bone sarcoma (n = 295) formed the analytic cohort. Metastases were classified as synchronous (≤6 months) or metachronous (>6 months), lung-only versus multi-organ, and oligometastatic (≤5 lesions, ≤2 organs) versus polymetastatic. TTME was illustrated with Kaplan–Meier curves for the full cohort (descriptive); where subgroup comparisons are shown, log-rank tests are reported. Results: Ninety-three patients (31.5%) developed metastases after a median follow-up of 20.9 months. Metastatic risk was front-loaded: 36.6% were synchronous, and 67.8% of metachronous events occurred within year 1. The lung was the initial site in 62.4% of events, bone in 18.3%, and liver in 11.8%. Half of the lung-metastatic patients remained pulmonary-confined; the remainder followed a multi-organ route involving bone and lymph nodes. Oligometastatic spread predominated in the lung-only subgroup (61%) versus multi-organ (28%). Histotype influenced both timing and tropism: angiosarcoma and Ewing sarcoma metastasized earliest (median 3.7 and 5.0 months) and multi-organ; leiomyosarcoma and UPS were lung-dominant; Ewing sarcoma and epithelioid haemangioendothelioma were bone-tropic; and angiosarcoma was liver-tropic. Conclusions: Metastatic sarcoma displays three intersecting dimensions—early versus late onset, organ-specific tropism, and oligo- versus polymetastatic burden—none of which are addressed by the current “one-size-fits-all” surveillance. Recognizing these patterns delineates windows for tailored imaging and stratified therapy selection (e.g., local ablation for oligometastatic lung disease, intensified systemic regimens for early, polymetastatic spread). These findings lay the groundwork for precision-adapted surveillance and treatment protocols. Pattern-stratified trials and health-economic evaluations are now needed to assess whether this approach improves outcomes and optimizes resource allocation. Full article

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

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19 pages, 4700 KB

Open AccessFeature PaperArticle

Cancer Growth and Invasion Are Increased in the Tight Skin (TSK) Mouse

by Maria Sol Recouvreux, Barbie Taylor-Harding, Amy C. Rowat, Beth Y. Karlan and Sandra Orsulic

Cancers 2025, 17(18), 2943; https://doi.org/10.3390/cancers17182943 - 9 Sep 2025

Abstract

Background: Patients with systemic sclerosis have a significantly increased incidence of developing various solid malignancies within a few years of systemic sclerosis onset, but the mechanism of tumor promotion is not well understood. The tight skin (TSK) mouse has been a valuable [...] Read more.

Background: Patients with systemic sclerosis have a significantly increased incidence of developing various solid malignancies within a few years of systemic sclerosis onset, but the mechanism of tumor promotion is not well understood. The tight skin (TSK) mouse has been a valuable model for investigating systemic sclerosis-related pathologies due to increased extracellular matrix deposition, fibrosis in connective tissues, and altered immune cell activation. Despite the role of extracellular matrix and fibrosis in cancer progression, the potential of the TSK mouse as a model for cancer studies is unexplored. Methods: To investigate the impact of the altered microenvironment in TSK mice on cancer progression, we compared the tumor-forming capabilities (by subcutaneous and intraperitoneal injection) in TSK mice and WT mice using syngeneic breast cancer, melanoma, and ovarian cancer cell lines. We used bulk and single-cell RNA sequencing to characterize these tumors and identify the changes in the TSK microenvironment that promote cancer formation. Results: In all three cancer types, TSK mice exhibited more invasive subcutaneous tumors in comparison to WT controls, underscoring the role of the TSK subcutaneous microenvironment in promoting cancer progression. Furthermore, the heightened invasiveness of ovarian tumors implanted intraperitoneally suggests that the peritoneal microenvironment in TSK mice also promotes tumor progression. Single-cell RNA sequencing analyses of subcutaneous tumors from TSK and WT mice revealed tumor-specific changes in the composition and phenotype of various cell populations. The most consistent alteration in TSK mice included a higher neutrophil-to-lymphocyte ratio and an enrichment in profibrotic subpopulations of myofibroblasts and macrophages. Conclusions: Our research unveils the TSK mouse as a valuable model for studying the intricate connections between systemic sclerosis and cancer Full article

(This article belongs to the Section Tumor Microenvironment)

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17 pages, 3336 KB

Open AccessArticle

Revealing the Angiogenic Signature of FH-Deficient Breast Cancer: Genomic Profiling and Clinical Implications

by Liat Anabel Sinberger, Noa Keren-Khadmy, Assaf Goldberg, Tamar Peretz-Yablonski, Amir Sonnenblick and Mali Salmon-Divon

Cancers 2025, 17(18), 2942; https://doi.org/10.3390/cancers17182942 - 9 Sep 2025

Abstract

Background: Fumarate hydratase (FH) deficiency is a rare metabolic alteration in breast cancer that may drive tumor progression through angiogenic remodeling. However, its role in shaping the tumor microenvironment remains poorly defined, limiting our understanding of metabolism-driven angiogenesis and its [...] Read more.

Background: Fumarate hydratase (FH) deficiency is a rare metabolic alteration in breast cancer that may drive tumor progression through angiogenic remodeling. However, its role in shaping the tumor microenvironment remains poorly defined, limiting our understanding of metabolism-driven angiogenesis and its therapeutic significance. Methods: We analyzed genomic and transcriptomic profiles from thousands of breast cancer samples, including the TCGA cohort, to identify FH mutations and copy number alterations. Differential expression, pathway enrichment, and weighted gene co-expression network analysis (WGCNA) were performed to characterize metabolic and signaling changes. Clinical relevance was examined in a triple-negative breast cancer patient with an FH mutation treated with bevacizumab. Results: FH alterations were enriched in larger, primary tumors and in older patients. FH-deficient tumors displayed metabolic reprogramming, with reduced oxidative phosphorylation and TCA cycle activity, accompanied by upregulation of angiogenesis, VEGF signaling, and epithelial–mesenchymal transition pathways. WGCNA identified 11 hub genes (including CDH5, CLDN5, VWF, and PECAM1) linked to a pro-angiogenic microenvironment. A clinical case illustrated a durable and exceptional response to bevacizumab-based therapy in an FH-mutant patient. Conclusions: FH deficiency promotes an angiogenic tumor microenvironment and may serve as a predictive biomarker for VEGF-targeted therapies. These findings underscore the therapeutic potential of exploiting metabolic vulnerabilities to inform precision oncology. Full article

(This article belongs to the Section Cancer Therapy)

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