Cancer Cell最新文献

{"title":"Chromatin accessibility trajectories reveal pre-cancerous epigenetic priming and an acid-driven immunotherapy-resistant gastric cancer subtype","authors":"Tao Wang,Junyu Xiang,Shuoran Tian,Xiangming Wang,Zhaole Chu,Zailiang Yang,Weiwu Gao,Xianfeng Li,Biying Liu,Qiang Ma,Zengjie Lei,Xiaochun Shen,Yinbin Zhou,Lei Wang,Linghong Wan,Quanyou Zheng,Wenkang Liu,Jinyang Li,Linyu Wu,Yongying Hou,Xipeng Zheng,Huilin Pan,Shixin Qin,Qin Liu,Mengting Sun,Xu Chen,Fanxuan Tian,Xiao Hu,Ziyi Peng,Zhaoyang Zhong,Chuan Chen,Fan Li,Shunan Wang,Dongfeng Chen,Liangzhi Wen,Ke Li,Qiaoqiao Zhang,Cheng Lin,Zhongyi Qin,Zhifeng Miao,Xiu-Wu Bian,Zhenning Wang,Fan Bai,Bin Wang","doi":"10.1016/j.ccell.2026.09.004","DOIUrl":"https://doi.org/10.1016/j.ccell.2026.09.004","url":null,"abstract":"","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"9 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090138","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 wu wei of brain metastases: When the gift of a pause is also a vulnerability","authors":"Anna Adam-Artigues,Deisy Segura-Villalobos,Julio A. Aguirre-Ghiso","doi":"10.1016/j.ccell.2026.09.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2026.09.007","url":null,"abstract":"In this issue of Cancer Cell, García-Gómez et al. show that brain-seeding cancer cells exploit an MXD4-dependent proliferative pause that enables survival under stress before metastatic outgrowth. By restraining MYC and activating protective stress responses, this pause becomes an Achilles’ heel, potentially targetable to eradicate micrometastases before clinical relapse.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"15 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067436","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":"A transient MXD4-dependent proliferative pause enables survival of brain micrometastases","authors":"Pedro García-Gómez,Diana Retana,Carolina Hernández-Oliver,Oliva Sánchez,Neibla Priego,Laura Álvaro-Espinosa,Lluís Cordón-Barris,Ana de Pablos-Aragoneses,Juan Vázquez-Cantó,Andrea Rojas,Catalina Vela-Gual,Beatriz Ocaña-Tienda,Samuel Morabito,Anna Pascual-Reguant,Pablo Sanz-Martínez,Manan Krishnamurthy,Ajit Kumar Sharma,Luise Rupp,Antonia Stammberger,Sara Carpintero,Rachel Scott,Carlos Garrido,María Gómez,María Isabel García,Kevin Troulé,Verona Villar-Cerviño,Guillermo Garaulet,Antonio Rodríguez,Srinivas Malladi,Nathan Beckouche,Eduardo Caleiras,Sandra Rodriguez-Perales,Raúl Torres-Ruiz,Fátima Al-Shahrour,Miguel Lafarga,PEACE Consortium,Monica Sivakumar,David A. Moore,Cristina Naceur-Lombardelli,Charles Swanton,Holger Heyn,Helen M. Byrne,Víctor M. Pérez-García,Anish Thomas,Marc Schmitz,Mariam Jamal-Hanjani,RENACER,Manuel Valiente","doi":"10.1016/j.ccell.2026.09.002","DOIUrl":"https://doi.org/10.1016/j.ccell.2026.09.002","url":null,"abstract":"Successful metastatic colonization requires cancer cells to survive multiple stresses during early organ adaptation, yet how metastasis-initiating cells overcome this bottleneck remains unknown. Here, we identify a transient MXD4-dependent proliferative pause that enables aggressive cancer cells to survive early brain colonization. Before vascular co-option-associated outgrowth, metastatic cells temporarily restrain proliferation through the MYC antagonist MXD4, buffering stresses encountered after extravasation. Genetic disruption of MXD4 compromises survival of micrometastases, preventing their progression to macrometastases. Analyses of human brain micrometastases validate this transient adaptive state in patients. Exploiting vulnerabilities associated with the proliferative pause reveals preventive therapeutic opportunities across experimental settings, including spontaneous brain metastasis models and minimal residual disease following neurosurgical resection. In addition, patient-derived organotypic cultures confirm the feasibility of targeting this state with clinically available drugs. These findings uncover a previously unrecognized adaptive stage during metastatic colonization and identify actionable vulnerabilities to prevent brain metastasis progression and relapse.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"75 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149067346","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":"Human-centric preclinical models for CAR T cell therapy in solid tumors: Where patient-derived organoids fit","authors":"Xiujian Ma,Julio Inocencio,Darya Alizadeh,Mohsen Basiri,Christine E. Brown","doi":"10.1016/j.ccell.2026.08.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2026.08.011","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy has shown promising activity in solid tumors, yet translational progress remains limited by preclinical models that incompletely capture human tumor biology. Patient-derived organoids (PDOs) preserve key features of human tumors, including cellular heterogeneity and tissue architecture, thereby enabling functional evaluation of CAR T cell targets, next-generation approaches, resistance mechanisms, and selected safety considerations. We discuss how PDOs complement existing preclinical platforms to support CAR T cell development for solid tumors.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"17 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149027569","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":"γδ T cells modulate anti-tumor immunity in small cell lung cancer","authors":"Jin Ng,Yue You,Tina Z. Zhang,Jonas B. Hess,Sarah A. Best,Alex Caneborg,Marcel Schmiel,Sarah T. Diepstraten,Tim Spelman,Joshua I. Gray,Dale I. Godfrey,Yin Wu,Richard W. Tothill,Casey J.A. Anttila,Tracey M. Baldwin,Shalin H. Naik,Daniela Amann-Zalcenstein,Ariena J. Kersbergen,Tracy L. Leong,Julie George,Matthew E. Ritchie,Nicholas A. Gherardin,Hui-Fern Koay,Peter F. Hickey,Daniel Steinfort,Kate D. Sutherland","doi":"10.1016/j.ccell.2026.08.015","DOIUrl":"https://doi.org/10.1016/j.ccell.2026.08.015","url":null,"abstract":"Small cell lung cancer (SCLC) is a highly aggressive neoplasm with limited sensitivity to anti-PD-(L)1 blockade, which is likely caused by the epigenetic silencing of MHC-I. Elucidating MHC-I-independent immune recognition mechanisms is therefore crucial for enhancing treatment responses and improving clinical outcomes in a greater number of patients. Leveraging single-cell approaches, we discovered γδ T cell infiltration in biospecimens from patients with SCLC. Despite PD-1 expression, γδ T cells maintained a cytotoxic transcriptional profile, suggesting an anti-tumor role. Indeed, high γδ T cell infiltration in two practice-changing clinical trials predicted improved response to anti-PD-L1 immunotherapy in patients with SCLC. Moreover, using preclinical models, we demonstrated that γδ T cells are effective at tarlatamab (delta-like ligand 3 [DLL3]-CD3 bispecific T cell engager [BiTE])-redirected SCLC killing and that zoledronate, an FDA-approved compound, can sensitize SCLC cells to γδ T cell-mediated killing. Thus, our findings suggest that engaged γδ T cells are potentially valuable targets for SCLC therapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"1 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148993757","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":"γδ T cells BiTE back at small cell lung cancer","authors":"David A. Hamilton,Mohindar M. Karunakaran,Seth B. Coffelt","doi":"10.1016/j.ccell.2026.08.016","DOIUrl":"https://doi.org/10.1016/j.ccell.2026.08.016","url":null,"abstract":"In this issue of Cancer Cell, Ng et al. characterize and leverage cytotoxic γδ T cells in small cell lung cancer to overcome unsuccessful checkpoint blockade immunotherapy. Engaging Vδ2+ cells with a bispecific T cell engager (BiTE) bypasses the challenge of low MHC-I expression and ineffective CD8+ T cells.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"84 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148993754","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":"Beyond genes and hotspots: Protein-informed interpretation of cancer mutations","authors":"Mei Luo,Leng Han","doi":"10.1016/j.ccell.2026.08.009","DOIUrl":"https://doi.org/10.1016/j.ccell.2026.08.009","url":null,"abstract":"Interpreting the biological and clinical significance of somatic mutations in cancer genomes remains challenging. In this issue of Cancer Cell, Hyeon et al. identify and map significantly mutated regions to protein domains and structural features, establishing a proteo-genomics framework for interpreting cancer mutations beyond genes and hotspots.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"47 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148980618","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":"Myeloid reprogramming generates myeloid-derived activating cells to potentiate radiotherapy and suppress metastasis","authors":"Fei Ji,Lei Zheng,Dapeng Chen,Peng Xia,Zhongyu Zou,Wei Liu,Jason Bugno,Emile Z. Naccasha,András Piffkó,Chuangyu Wen,Kangdi Li,Liping Xu,Sean Z. Luo,Xiaona Huang,Jiaai Wang,Chengwei Ju,Bei Liu,Yiyi Ji,Han Li,Steven J. Chmura,Sean P. Pitroda,Hua Laura Liang,Chuan He,Ralph R. Weichselbaum","doi":"10.1016/j.ccell.2026.08.017","DOIUrl":"https://doi.org/10.1016/j.ccell.2026.08.017","url":null,"abstract":"Radiation induces immunosuppressive myeloid cells that drive therapeutic resistance and metastasis. We identify TET2 as a radiation-induced regulator of myeloid-derived suppressor cells whose expression correlates with poor outcomes in advanced lung cancer patients receiving radio-immunotherapy. Following radiotherapy, myeloid-specific Tet2 deletion suppresses tumor progression and redirects monocyte differentiation toward antigen-presenting myeloid-derived activating cells (MDACs), which augment antitumor T cell responses; spatiotemporal mapping shows that this fate program initiates rapidly in the bone marrow. Mechanistically, a radiation-responsive p53-TET2 axis decreases m5C on chromatin-associated RNAs (caRNAs), enforcing immunosuppressive chromatin compaction and silencing interferon signaling, whereas Tet2 loss restores chromatin accessibility and enhances CD8+ T cell cytotoxicity. Pharmacological TET2 inhibition recapitulates this phenotype and augments radiotherapy and PD-L1 blockade to control primary and metastatic tumors. These findings define MDACs as an immunogenic myeloid subset and establish myeloid reprogramming as a strategy to improve radiotherapy-immunotherapy outcomes.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"1 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148980620","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":"Chemotherapy-free phase 1/2 trial of HRS-4642 plus adebrelimab in previously treated metastatic KRAS G12D-mutant pancreatic cancer","authors":"Si Shi,Miaoyan Wei,Nan Du,Jialin Li,Boyue Han,Wei Wang,Xin Hu,Fei Luo,Jin Xu,Xianjun Yu","doi":"10.1016/j.ccell.2026.08.012","DOIUrl":"https://doi.org/10.1016/j.ccell.2026.08.012","url":null,"abstract":"KRAS G12D mutations drive approximately 40% of pancreatic ductal adenocarcinoma (PDAC) cases and foster an immunosuppressive tumor microenvironment. This phase 1/2 trial (NCT06427239) evaluated HRS-4642, a selective KRAS G12D inhibitor, combined with the PD-L1 blockade adebrelimab in 48 pretreated patients with metastatic KRAS G12D-mutant PDAC. Dose escalation revealed no dose-limiting toxicities, establishing the recommended phase 2 dose (RP2D), and no treatment-related deaths occurred; hypercholesterolemia and anemia (each 50%) were the most common treatment-related adverse events. In the RP2D cohort (n = 37), the confirmed objective response rate was 43.2% (95% confidence interval [CI], 27.1–60.5), disease control rate was 81.1% (95% CI, 64.8–92.0), median duration of response was 6.9 months (95% CI, 4.8–8.6), median progression-free survival was 5.7 months (95% CI, 4.0–7.5), and median overall survival was 11.5 months (95% CI, 9.2–16.9). This chemotherapy-free regimen is tolerable and shows encouraging antitumor activity in refractory KRAS G12D-mutant PDAC, warranting further investigation.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"59 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148973456","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":"Chronotherapy with immune checkpoint inhibitors: The knowns, the unknowns, and the contested","authors":"Zeynep Melis Gül,Qun Zeng,Doron Merkler,Christoph Scheiermann","doi":"10.1016/j.ccell.2026.08.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2026.08.010","url":null,"abstract":"Emerging data indicate that immune checkpoint inhibitors can exhibit time-of-day-dependent effects in pre-clinical models. Furthermore, multiple retrospective clinical trials associate earlier anti-tumor treatment timing with improved outcomes. However, key questions remain regarding the reproducibility of these findings, the underlying mechanisms, and their clinical implications. This commentary discusses these open questions and provides an outlook on the field.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"59 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148964389","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}