British Journal of Cancer最新文献

{"title":"Risk prediction model for brain metastasis risk among patients diagnosed with primary gastrointestinal cancers.","authors":"Marc Vincent N Barcelona, Kaushik Jagannath Kataki, Fadwa Abdel Rahman, Fabio Y Moraes, Barbara Ann Millar, Tatiana Conrad, Dana Keilty, Andrew Hope, Alexander Sun, Paul Kongkham, Elena Elimova, Yangqing Deng, David Shultz, Michael Yan","doi":"10.1038/s41416-026-03587-8","DOIUrl":"https://doi.org/10.1038/s41416-026-03587-8","url":null,"abstract":"<p><strong>Background: </strong>The risk of radiotherapy-treated brain metastasis (BrM) in gastrointestinal (GI) cancers is poorly defined. We aimed to determine its incidence and develop a clinically interpretable prediction model.</p><p><strong>Methods: </strong>Patients with GI cancers diagnosed between 2005-2020 were identified from our registry. Receipt of brain radiotherapy was used to define radiotherapy-treated BrM. Logistic regression was performed on a training cohort to identify BrM predictors, which were then used to construct a risk score, and validate performance in a held-out cohort. Model performance was assessed with receiver operating characteristic (ROC) analysis, calibration, Brier score, and Multiple imputation by chained equations (MICE) sensitivity analysis.</p><p><strong>Results: </strong>Among 14,863 eligible patients, the 15-year cumulative incidence of clinically treated BrM was 1.89%. Median OS following BrM was 3.7 months. Logistic regression was performed in 11,022 patients with complete data. In the complete-case training cohort (n = 7348), significant predictors included primary site, clinical stage, chemotherapy, and recurrence at presentation. The AUC was 0.80, with good calibration and Brier score 0.012. Medium- and high-risk groups had higher BrM risk in validation (HR 4.57 and 11.35, respectively).</p><p><strong>Conclusions: </strong>We developed an internally validated prediction model for BrM in GI cancers. External validation is required.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148825080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oligometastatic neuroendocrine tumours: imprecision is not equivalence","authors":"Qu Zhang","doi":"10.1038/s41416-026-03604-w","DOIUrl":"10.1038/s41416-026-03604-w","url":null,"abstract":"","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"135 7","pages":"1022-1022"},"PeriodicalIF":7.8,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148824952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of DNA mismatch repair status in oesophagogastric cancer treated with perioperative chemotherapy: evidence from the MRC ST03 and OE05 trials.","authors":"Panagiotis Ntellas, Tom Lund, Georgina A Keogh, Manuel Salto-Tellez, Katharina von Loga, Tatiany Silveira, Susanna Riisnaes, Jon Laye, Ruth E Langley, Matthew G Nankivell, William H Allum, Avani Athauda, David Cunningham, Heike I Grabsch","doi":"10.1038/s41416-026-03594-9","DOIUrl":"https://doi.org/10.1038/s41416-026-03594-9","url":null,"abstract":"<p><strong>Background: </strong>Mismatch repair deficiency (MMRd) is a key determinant of tumour biology, however, its prognostic significance in patients with resectable oesophagogastric adenocarcinoma treated with perioperative cytotoxic chemotherapy remains uncertain.</p><p><strong>Methods: </strong>MMR status was assessed in 1424 patients with oesophagogastric adenocarcinoma enroled in the MRC OE05 and ST03 trials, which investigated perioperative chemotherapy regimens. Associations between MMR status, clinicopathological variables, overall survival (OS), progression-free survival (PFS) and post-progression survival (PPS) were investigated.</p><p><strong>Results: </strong>In total, 78 (5.5%) tumours were MMRd, 80.8% due to MLH1 loss. Patients with MMRd tumours had improved OS compared with patients with MMR proficient (MMRp) tumours (median unreached vs 28.0 months; p = 0.0009; 5-year rates 50.1% vs. 34.3%), and PFS (median 56.7 vs 21.4 months; p = 0.0032). On multivariable analysis, MMRd remained associated with improved OS (HR 0.60, 95% CI 0.42-0.87; p = 0.007) and PFS (HR 0.64, 95% CI 0.45-0.90; p = 0.011). PPS did not differ by MMR status.</p><p><strong>Discussion: </strong>This is the first study to suggest that perioperative cytotoxic chemotherapy does not abrogate the favourable prognostic impact of MMRd prior to disease progression. However, MMR status did not influence survival after progression. Our results challenge clinical concerns that cytotoxic chemotherapy may be detrimental in patients with resectable MMRd oesophagogastric adenocarcinoma.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer and Health Inequalities","authors":"Donna Wakefield,&nbsp;Clare Bambra","doi":"10.1038/s41416-026-03599-4","DOIUrl":"10.1038/s41416-026-03599-4","url":null,"abstract":"Cancer is subject to stark inequalities, with mortality rates 60% higher in the most deprived parts of the UK. Most research has focused on the role of behavioural risk factors or access to health care services. Insufficient attention has been paid to the influence of socio-economic factors across the whole cancer continuum. This essay argues that to reduce cancer inequalities and improve patient experience and clinical outcomes, we need to look more widely at inequalities in: (1) the risk of developing cancer; (2) the effectiveness of prevention, detection and diagnosis; (3) treatment; (4) survivorship, and (5) access to palliative care. We argue that a stronger awareness and understanding of the influence of the wider social, economic and cultural context of health can enable clinicians to improve the delivery of more equitable cancer care. We conclude by recommending ways forward to improve the cancer continuum for everyone.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"135 9","pages":"1361-1364"},"PeriodicalIF":7.8,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-026-03599-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-oxygen pancreatic cancer organoids recapitulate basal-classical heterogeneity validated by spatial transcriptomics.","authors":"Koichiro Kumano, Hiromitsu Nakahashi, Osamu Shimomura, Yoshimasa Akashi, Yoshihiro Miyazaki, Yohei Owada, Shinji Hashimoto, Kazuto Kamohara, Shuhei Komatsuzaki, Yukihito Kuroda, Jaejeong Kim, Pakavarin Louphrasitthiphol, Colin R Goding, Yoshiaki Abe, Mamiko Sakata-Yanagimoto, Noriaki Sakamoto, Daisuke Matsubara, Ayako Suzuki, Yutaka Suzuki, Tatsuya Oda","doi":"10.1038/s41416-026-03577-w","DOIUrl":"https://doi.org/10.1038/s41416-026-03577-w","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) comprises heterogeneous classical and basal-like subtypes. Although pancreatic cancer organoids (PCOs) are widely used, normoxic cultures preferentially maintain the classical subtype, limiting their ability to represent intrinsic intratumoral heterogeneity. Because PDAC develops in profoundly hypoxic microenvironments, the influence of oxygen tension on organoid modelling remains unclear.</p><p><strong>Methods: </strong>We performed spatially resolved single-cell transcriptomics on 12 primary PDAC tumours to map the distributions of classical and basal-like cells. Paired organoids were generated under normoxic (20% O₂; NORM-PCOs) and hypoxic (1% O₂; HYPO-PCOs) conditions, and morphology, subtype scores, proliferation and drug responses were compared.</p><p><strong>Results: </strong>Spatial profiling revealed gradients of basal-like-classical heterogeneity across tumours, with basal-like cells enriched in hypoxic regions. HYPO-PCOs tended to retain basal-like traits, including solid or multi-layered morphology, and increased proliferation, along with a tendency toward reduced sensitivity to chemotherapeutic agents. In contrast, NORM-PCOs more often exhibited mono-layered morphology and showed higher classical subtype scores.</p><p><strong>Conclusions: </strong>Hypoxic culture conditions promote the preservation of basal-like subpopulations in PDAC organoids, more accurately reflecting the basal-classical heterogeneity of primary tumours. Hypoxia-induced basal-like features remained stable after oxygen switching, indicating a fixed phenotype that informs organoid modelling and offers insight into PDAC progression.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategic roadmap for delivery of clinical trials in rare childhood central nervous system (CNS) tumours: a multi-stakeholder consensus","authors":"Jenny Adamski,&nbsp;John R. Apps,&nbsp;Sarita Depani,&nbsp;Rebecca M. Hill,&nbsp;Barry Pizer,&nbsp;Thankamma Ajithkumar,&nbsp;Simon Bailey,&nbsp;Kim S. Bull,&nbsp;Fernando Carceller,&nbsp;Julia V. Cockle,&nbsp;Robert A. Dineen,&nbsp;Jessica A. Douglas‑Pugh,&nbsp;Jenny Gains,&nbsp;Debbie Hicks,&nbsp;Mette Jorgensen,&nbsp;John-Paul Kilday,&nbsp;Juan-Pedro Martinez‑Barbera,&nbsp;Timothy A. Ritzmann,&nbsp;Emma Thompson,&nbsp;Simon Gates,&nbsp;Darren Hargrave,&nbsp;Allan Hackshaw,&nbsp;G. A. Amos Burke,&nbsp;Steven C. Clifford","doi":"10.1038/s41416-026-03589-6","DOIUrl":"10.1038/s41416-026-03589-6","url":null,"abstract":"Rare paediatric central nervous system (CNS) tumours comprise a biologically-heterogeneous group of low-incidence diseases that present significant challenges to both therapeutic development and clinical research, limiting the availability of high-quality evidence to guide clinical care. The UK3CR Children’s Cancer Research Group (CRG) CNS Tumours Subgroup convened a multidisciplinary workshop to identify research priorities and establish a strategic framework for advancing clinical trials in this setting. Four high-priority tumour groups—craniopharyngioma, choroid plexus carcinoma (CPC), very high-risk medulloblastoma (VHR-MB), and rare embryonal and sarcomatous tumours (REST), including embryonal tumour with multilayered rosettes (ETMR)—were evaluated. Key outcomes included the feasibility of a UK-led craniopharyngioma trial, the need for enhanced national CPC data collection, and support for European early-phase platform trials in VHR-MB. REST highlighted transnational regulatory complexity requiring coordinated registries and parallel trial models. Cross-cutting barriers included regulatory discordance, contracting delays, fragmented funding, pharmacovigilance differences, data-sharing constraints, and interoperable infrastructures. The workshop emphasised innovative methodologies, including Bayesian/adaptive designs, platform trials, and external control arms, to maximise efficiency in small populations, alongside strengthened patient involvement and international collaboration. Collectively, these findings define a collaborative and internationally-aligned strategic roadmap to accelerate clinical research and improve outcomes in rare paediatric CNS tumours.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"135 8","pages":"1183-1193"},"PeriodicalIF":7.8,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-026-03589-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A deep learning-derived risk score model from digital pathology to forecast nivolumab outcomes in gastric carcinoma.","authors":"Yiyu Hong, Inwoo Hwang, Min-Ji Kim, Yuyeon Kim, Soomin Ahn, Jeeyun Lee, Kyoung-Mee Kim","doi":"10.1038/s41416-026-03590-z","DOIUrl":"https://doi.org/10.1038/s41416-026-03590-z","url":null,"abstract":"<p><strong>Background: </strong>The PD-L1 combined positive score (CPS) is a biomarker predicting responses in gastric cancer (GC) immunotherapy.</p><p><strong>Objectives: </strong>We aimed to develop a deep learning-based model to predict responses to nivolumab in GC using PD-L1 28-8 immunohistochemistry.</p><p><strong>Methods: </strong>A cell-detection network was trained on 1927 patches from 88 whole-slide images to generate a computational positive cell ratio (cPCR). The predictive performance of cPCR was evaluated in an independent cohort of 147 patients treated with nivolumab plus chemotherapy.</p><p><strong>Results: </strong>The overall objective response rate (ORR) was 49.66%. ORR was 56.12% in patients with PD-L1 CPS ≥ 5 and 36.73% in those with CPS < 5. Using cPCR, ORR was 56.03% for cPCR ≥5 and 25.81% for cPCR <5. The AUCs of CPS (0.586) and cPCR (0.601) did not differ significantly, but net reclassification analysis showed superior predictive performance for cPCR (p = 0.0269). Incorporating cPCR with tumour-stroma ratio through stepwise variable selection enabled construction of a risk-score model that improved prediction of immunotherapy benefit.</p><p><strong>Conclusions: </strong>In conclusion, we developed a cPCR-based model and risk-score system that more accurately forecasts nivolumab response in GC, offering a promising tool for optimising immunotherapy selection.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of orphan G protein-coupled receptor GPR52 in breast cancer cell multicellular organization and collective invasion.","authors":"Sarah Z Hanif, Caleb Kutz, CheukMan Cherie Au, Ingrid Torregroza, Sailesh Palikhe, Syeda Y Jannath, Tabassum Fabiha, Bhavneet Bhinder, Michael P Washburn, Dominic Devost, Shuchen Liu, Priya Bhardwaj, Todd Evans, Xiaobo Liang, Pradeep Kumar Anand, Robert Tarran, Olivier Elemento, Lukas E Dow, John Blenis, Terence E Hébert, Kristy A Brown","doi":"10.1038/s41416-026-03565-0","DOIUrl":"10.1038/s41416-026-03565-0","url":null,"abstract":"<p><strong>Background: </strong>G protein-coupled receptors (GPCRs) are the largest class of membrane-bound receptors and are emerging as targets for the effective treatment of cancer. The role of orphan GPCR GPR52 in cancer has not been characterized. Low mRNA expression of GPR52 in breast tumours correlates with reduced overall survival, leading to the hypothesis that loss of GPR52 supports breast cancer progression.</p><p><strong>Methods: </strong>CRISPR-Cas9 was used to knock out GPR52 in the human triple-negative breast cancer cell lines MDA-MB-468 and MDA-MB-231. 2D and 3D in vitro studies, electron microscopy, and a zebrafish xenograft model were used to assess the morphology and behaviour of GPR52 KO cells.</p><p><strong>Results: </strong>Loss of GPR52 was associated with elevated levels of cAMP, increased cell-cell interaction in 2D cultures, more spindle-like morphology on collagen, altered 3D spheroid morphology, and increased propensity to organize and invade collectively. Zebrafish injected with GPR52 KO cells developed a greater total cancer area than control. RNA sequencing and proteomic analyses of GPR52-null cells revealed an increased cAMP signalling signature. Re-expression of GPR52 and inhibition of cAMP production rescued some GPR52 KO phenotypes.</p><p><strong>Conclusions: </strong>GPR52 loss is a potential mechanism by which breast cancer progression may occur and supports the investigation of GPR52 agonism as a therapeutic option for breast cancer.</p><p><strong>Statement of significance: </strong>Loss of the orphan GPCR GPR52 in human breast cell lines leads to increased cell clustering, hybrid/partial EMT, and increased tumour burden in zebrafish, further expanding our understanding of mechanisms driving cancer progression and opening the door to novel therapeutic approaches.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD39⁺CD103⁺CD8⁺ T cells enhance neoadjuvant chemoimmunotherapy efficacy in head and neck squamous cell carcinoma.","authors":"Suling Chen, Yupeng Wu, Guangxin Rao, Weihao Tong, Jingbin Huo, Guoxin Huang, Wenhao Sun, Songjiu Li, Chenchang Li, Shengguo Hu, Yingnan Ma, Ruiqi Zhu, Diya Wang, Meijuan Zhang, Qi'an Chen, Xiao Tan, Jinsong Li, Zhaoyu Lin, Bowen Li","doi":"10.1038/s41416-026-03588-7","DOIUrl":"https://doi.org/10.1038/s41416-026-03588-7","url":null,"abstract":"<p><strong>Background: </strong>Neoadjuvant chemoimmunotherapy (NACI) has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment. However, some patients still do not respond significantly, partly attributed to insufficient anti-tumor specific T-cells. Thus, identifying the underlying causes of impaired antitumor immunity has become an urgent priority to improve efficacy.</p><p><strong>Methods: </strong>To investigate the link between anti-tumor specific T cells and NACI efficacy in treating HNSCC, we employed multicolor immunohistochemistry (mIHC) and single-cell RNA sequencing (scRNA-seq). To gain deeper insights into the regulatory mechanisms of these T cell populations, we performed cell-cell interaction analysis and spatial analysis. Furthermore, co-culture experiments were carried out to explore the interactions between the cells.</p><p><strong>Results: </strong>Our scRNA-seq results indicated that the population of CD39⁺CD103⁺ (double-positive, DP) CD8⁺ T cells was dramatically increased in the responders of NACI-treated HNSCC patients, while mIHC analysis confirmed the correlation between DP CD8⁺ T cells density and NACI response. Functional assays demonstrated that DP CD8⁺ T cells constitute a distinct T cell subset exhibiting enhanced cytotoxic activity. The cell-cell interaction analysis revealed that DP CD8⁺ T cells were regulated by the CD90⁺CD138⁺ cancer-associated fibroblasts (CAFs) subset, which has been characterized as desmoplastic CAFs (dCAFs). In vitro mechanistic experiments suggested that CD90⁺CD138⁺ CAF-derived LAMA-4 may reduce the antitumor capacity of DP CD8⁺ T cells.</p><p><strong>Conclusions: </strong>Our study highlights the critical role of DP CD8⁺ T cells in enhancing NACI efficacy. Meanwhile, further research is warranted to explore the effects of targeting CD90⁺CD138⁺ CAFs,a thus regulating the function of DP CD8⁺ T cells.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kdm2a histone demethylase ablation restores anti-tumor immunogenicity in liver cancer.","authors":"Laura Gragnani, Matteo Lulli, Patrizio Caini, Pinuccia Faviana, Rossella Del Frate, Enrico Desideri, Katia De Ieso, Francesco Bartoli, Andrew Hall, Tu Vinh Luong, Krista Rombouts, Vinicio Carloni","doi":"10.1038/s41416-026-03566-z","DOIUrl":"https://doi.org/10.1038/s41416-026-03566-z","url":null,"abstract":"<p><strong>Background: </strong>Liver cancer remains a major global challenge, with limited benefit from immune checkpoint inhibitors due to strong immune evasion. Emerging evidence indicates that chromatin modifiers shape tumor immunogenicity, but their roles in liver cancer immunity are not fully understood.</p><p><strong>Methods: </strong>We investigated the role of the histone demethylase KDM2A in liver cancer using genetic silencing in vitro and in vivo. We evaluated mitochondrial function, redox balance, genomic stability, and performed transcriptomic and epigenomic analyses to assess immune pathway changes and H3K36me2 distribution. Immune infiltration was analyzed in human liver tumors and syngeneic mouse models.</p><p><strong>Results: </strong>KDM2A silencing caused mitochondrial dysfunction, redox imbalance, and DNA damage, leading to activation of innate and adaptive immune pathways. It also reshaped H3K36me2 deposition at loci regulating chemokine signaling, metabolism, and T-cell recruitment. In human liver tumors, high KDM2A expression correlated with poor differentiation, macrophage enrichment, and exclusion of CD8⁺ T cells, consistent with an immune-excluded phenotype. In syngeneic models, KDM2A loss increased intratumoral CD8⁺ T-cell infiltration.</p><p><strong>Conclusions: </strong>KDM2A acts as a key epigenetic regulator of mitochondrial function, genomic stability, and the tumor immune microenvironment in liver cancer. Targeting KDM2A may enhance tumor immunogenicity and improve responses to immunotherapy, representing a promising therapeutic strategy.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}