Cancer Cell最新文献

{"title":"Spatial biomarker discovery via interpretable semantic learning in histopathology.","authors":"Junhao Liang, Xiaofeng Jiang, Nic Gabriel Reitsam, Tim Lenz, Li Zhang, Marco Gustav, Zunamys Itzell Carrero, Hannah Sophie Muti, Peter Neidlinger, Jan Clusmann, Laura Žigutytė, Vidhya Sainath, Fabian Wolf, Lisa A Boardman, Amy J French, Ellen L Goode, Andrea Gsur, Stefanie Brezina, Marc J Gunter, Robert Steinfelder, Tabitha Harrison, Ulrike Peters, Amanda I Phipps, Philip Quirke, Nicholas P West, Michael Hoffmeister, Hermann Brenner, Durgesh Wankhede, Jitendra Jonnagaddala, Nicholas Hawkins, Robyn L Ward, Elena Fountzilas, Kyriaki Papadopoulou, George Fountzilas, Thierry André, Julien Taieb, Jean-François Emile, Magali Svrcek, Lingjie Kong, Jakob Nikolas Kather","doi":"10.1016/j.ccell.2026.05.014","DOIUrl":"10.1016/j.ccell.2026.05.014","url":null,"abstract":"<p><p>Spatial biomarkers are critical for precision oncology but remain challenging to systematically discover due to the complexity of whole-slide images. We present PathPrism, an interpretable AI framework for spatial biomarker discovery and virtual experimentation. Unlike black-box models, PathPrism encodes tissue architecture into pathologically informed spatial features, enabling transparent modeling of prognosis, molecular alterations, and therapy response. Applied to 7,000 patients with colorectal cancer across 11 cohorts, PathPrism uncovered hundreds of biomarkers predictive of survival, MSI, BRAF, and TP53 mutations, and stratified chemotherapy benefit in stage II/III disease. Building on these interpretable findings, PathPrism uses large language models as auxiliary tools to generate hypotheses grounded in spatial semantics. We further introduce VirtualWSI, a platform for semantic perturbation within an interpretable spatial biomarker atlas. PathPrism provides a scalable and interpretable framework for spatial biomarker discovery.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1605-1622.e7"},"PeriodicalIF":56.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223379","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":"Your neighbors matter: Adjacent cancer cells dampen TLS function.","authors":"Nicholas J Salgia, Jason B Muhitch","doi":"10.1016/j.ccell.2026.06.011","DOIUrl":"10.1016/j.ccell.2026.06.011","url":null,"abstract":"<p><p>In this issue of Cancer Cell, Hernández-Verdin et al. reveal why some tumors with tertiary lymphoid structures (TLSs) resist immunotherapy: their findings identify cancer-derived gamma-aminobutyric acid (GABA) as an immunosuppressant factor resulting in dysfunctional TLS and immunotherapy resistance. Targeting GABA with immunotherapy reshapes the tumor and TLS microenvironment and ultimately improves therapeutic efficacy.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1533-1535"},"PeriodicalIF":56.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419065","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":"Mapping micrometastatic seeds of relapse.","authors":"Hui Ting Grace Yeo, Iain Beehuat Tan","doi":"10.1016/j.ccell.2026.07.007","DOIUrl":"10.1016/j.ccell.2026.07.007","url":null,"abstract":"<p><p>In this issue of Cancer Cell, Liu et al. apply spatial multi-omics to map colorectal cancer micrometastases across primary tumors and matched liver and lung metastases, revealing liver micrometastases as an early evolved, stem-like, immune-suppressed residual disease state linked to a six-gene recurrence signature.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1539-1541"},"PeriodicalIF":56.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648314","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":"Subclinical cholestasis is a hallmark of gut dysbiosis causing resistance to cancer immunotherapy.","authors":"Anne-Laure Mallard de La Varende, Ai-Ling Tian, Simon Thomas, Imran Lahmar, Meriem Messaoudene, Sijing Li, Omar Motiño, Hortense Guillaume-Dit-Taunière, Valerio Iebba, Yoan Hurtado, Thao-Nguyen Pham, Cassandra Thélémaque, Miguel Araujo-Voces, Deborah Suissa, Pierre Ly, Ella Reich, Giacomo Vitali, Bryan Thierry Arlunno, Sylvere Durand, Fanny Aprahamian, Marion Leduc, Sabrina Forveille, Oliver Kepp, Carlos de la Calle-Fabregat, Angela Schippers, Norbert Wagner, Pierre-Edouard Fournier, Kenya Honda, Federica Marmorino, Chiara Cremolini, Saman Maleki Vareki, John G Lenehan, Aurélien Marabelle, François-Xavier Danlos, Margaux Deligne, Caroline Truntzer, François Ghiringhelli, Anne H Ree, Paula A Bousquet, Sebastian Meltzer, Florent Ginhoux, Deklan Rummel, Yousi Fu, Robert A Quinn, Carolina Alves Costa Silva, Roberto Iacovelli, Chiara Ciccarese, Serena Porcari, Arielle Elkrief, Bertrand Routy, Gianluca Ianiro, Lisa Derosa, Guido Kroemer, Marine Fidelle, Laurence Zitvogel","doi":"10.1016/j.ccell.2026.06.022","DOIUrl":"10.1016/j.ccell.2026.06.022","url":null,"abstract":"<p><p>Gut dysbiosis compromises cancer immunosurveillance by downregulating ileal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but the metabolic landscape associated with gut dysbiosis remains elusive. Here, we show that antibiotics (ABX) or ABX-associated Enterocloster species lead to the loss of secondary bile acids (BAs) including deoxycholic acid (DCA) and the accumulation of tauro-conjugated primary BAs (tauro-chenodeoxycholic acid [TCDCA] and tauro-β-muricholic acid [T-βMCA]) from the alternative pathway in the plasma of patients and mice. Fecal microbial transplantation (FMT), the ileum-specific farnesoid X receptor (FXR) agonist fexaramine, or glycodeoxycholic acid (GDCA) compensated dysbiosis-associated BA abnormalities and circumvent primary resistance to PD-1 blockade. GDCA curtailed ABX-induced MAdCAM-1 downregulation and T cell exhaustion in tumors. Subclinical cholestasis defined by elevation of γ-glutamyl transferase (γGT) correlated with increased TCDCA and decreased soluble MAdCAM-1 in plasma and predicted poor survival in multivariate analyses in six cohorts of patients who received immunotherapy. Hence, subclinical cholestasis accompanies gut dysbiosis, paving the way to immunoresistance.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1653-1671.e16"},"PeriodicalIF":56.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13471043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618526","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":"Macrophage-mediated brain-bone marrow crosstalk promotes chronic stress-induced glioma growth.","authors":"Zhengnan Yang, Jingtian Zhou, Fan Fei, Bohao Zheng, Sophie Xin Yang, Thomas M Pearce, Peidong Zhang, Liang Huang, Jing Yue, Qiuhong Shen, Yiwei Du, Xiaoling Liao, Siyu Cheng, Li Li, Jian Liang, Luyao Liu, Xiaoxiao Wan, Michael D Taylor, Joseph R Ecker, Shengtao Zhou, Jeremy N Rich, Linjie Zhao","doi":"10.1016/j.ccell.2026.05.018","DOIUrl":"10.1016/j.ccell.2026.05.018","url":null,"abstract":"<p><p>Stress is associated with increased cancer morbidity and mortality. Here, we show that chronic stress accelerates glioma growth and reduces survival of tumor-bearing mice. Integrated multi-omics analysis of syngeneic glioma samples reveals stress-induced CD45⁺CD11b⁺C5aR1⁺ macrophages, termed stress-associated macrophages (SAMs). Using parabiosis experiments in mice, we demonstrate that SAMs are derived from bone marrow monocytes. Stress-activated sympathetic nerve promotes the differentiation of ADRB2⁺ bone marrow monocytes into SAMs, which can be antagonized by selective ablation of catecholaminergic nerves. Conditional knockout of C5ar1 in macrophages, or pharmacologic C5aR inhibition, reduces SAMs and attenuates stress-induced glioma tumor growth in vivo. SAMs exhibit elevated CD36 expression, leading to excessive intracellular lipid accumulation and peroxidization, dampening their phagocytotic capacity. SAMs abundance correlates with self-reported stress levels and portended prognosis in glioma patients. Collectively, these findings suggest that stress reprograms tumor immune microenvironment by inducing molecularly distinguished monocyte-derived macrophages, revealing potential opportunities for immune-based cancer therapies.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1587-1604.e7"},"PeriodicalIF":56.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148276199","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":"Mapping cell type-resolved transcriptomic profiles to patient survival in pancreatic cancer.","authors":"Rong Tang, Liquan Jin, Chen Chen, Yingna Liao, Dingru Li, Yangyi Li, Yueyue Chen, Yuan Liu, Qiong Du, Zeyin Rong, Jiaoshun Chen, Yubin Lei, Zijian Wu, Zhen Tan, Yufeng Wang, Haoyu Wang, Jin Xu, Wei Wang, Si Shi, Xianjun Yu","doi":"10.1016/j.ccell.2026.05.012","DOIUrl":"10.1016/j.ccell.2026.05.012","url":null,"abstract":"<p><p>Traditional bulk-level transcriptomic sequencing cannot link cell type-specific gene expression to patient survival. In this study, we integrate single-nucleus RNA-seq and longitudinal data from 152 patients with pancreatic ductal adenocarcinoma (PDAC), profiling 1.2 million cells to construct a prognostic map connecting cell type-resolved gene expression with overall survival. Using a single-cell-resolved spatial transcriptomic platform, we further analyze 3.1 million cells and correlate their spatial distribution with therapeutic response. To empower the translational research community, we develop ctPANDA, an interactive platform offering cell-type-level prognostic insights. This atlas identifies PLOD2 as a promising target, with elevated expression predicting poorer outcomes across eight cell types. We have developed a proof-of-concept compound that can effectively degrade PLOD2 and inhibit PDAC progression in vivo. Collectively, this study advances the prognostic analysis from bulk-level to cell-type resolution, establishing a framework linking gene expression to clinical outcomes and providing actionable insights for target discovery and precision oncology.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1623-1638.e11"},"PeriodicalIF":56.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223394","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":"GABA promotes resistance to immunotherapy in patients with TLS-positive tumors.","authors":"Isaias Hernández-Verdin, Anne Calvez, Cheng-Ming Sun, Antoine Bougoüin, Pierre Hirt, Eric Pinaud, Matthew J Smith, Craig E Wheelock, Virginie Verkarre, Yann-Alexandre Vano, Lucie Garnier, Théo Bouloudani, Guilhem Pupier, Dahbia Djaroun, Christian Wu, Asmat Ullah, Lucile Vanhersecke, Alban Bessede, Jean-Philippe Guegan, Laurence Albiges, Sylvère Durand, Guido Kroemer, Agusti Alentorn, Antoine Italiano, Stéphane Oudard, Catherine Sautès-Fridman, Wolf Herman Fridman","doi":"10.1016/j.ccell.2026.06.006","DOIUrl":"10.1016/j.ccell.2026.06.006","url":null,"abstract":"<p><p>Tertiary lymphoid structures (TLSs) correlate with favorable responses to immune checkpoint inhibitors (ICIs) in various cancers, yet many patients with TLS-positive tumors are resistant to treatment. Multi-omic profiling of clear cell renal cell carcinoma (ccRCC) and soft tissue sarcoma tumors (STSs) reveals an upregulation of gamma-aminobutyric acid (GABA)-related signatures in non-responders to ICIs. In ccRCC, TLSs from non-responders located near GABA-producing tumor cells exhibit impaired B cell maturation, reduced IgG production, higher GABA receptor expression, and tricarboxylic acid cycle activation. In vitro, exposure of human B cells to GABA reduces HLA-DR expression, proliferation, and immunoglobulin secretion by receptor-independent and dependent mechanisms. Pharmacological inhibition of GABA-synthesis increases ICI response and immune infiltration, particularly by B cells, in a TLS-positive STS mouse model. Our findings unravel GABA as an immunoregulatory metabolite and provide a rationale for its therapeutic targeting to overcome ICI resistance in patients with TLS-positive tumors.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1685-1703.e14"},"PeriodicalIF":56.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419057","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 Terry Fox Research Institute Marathon of Hope Cancer Centres Network: A pan-Canadian precision oncology initiative.","authors":"","doi":"10.1016/j.ccell.2026.07.002","DOIUrl":"10.1016/j.ccell.2026.07.002","url":null,"abstract":"","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1714"},"PeriodicalIF":56.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454794","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":"Perioperative tislelizumab plus chemotherapy for locally advanced gastric cancer: A randomized, prospective phase 2 trial.","authors":"Zhiyuan Xu, Can Hu, Litao Yang, Pengfei Yu, Yanqiang Zhang, Jiahui Chen, Guoliang Zheng, Xiaodong Chen, Tao Zhang, Weiyang He, Xiangyu Meng, Panpan Yu, Yian Du, Xiaowen Liu, Youdong Liu, Yongxiang Wang, Xiaoxiao Wu, Siwei Pan, Ruolan Zhang, Shengjie Zhang, Zhirong Xiong, Wei Sun, Chuanxin Dong, Jiajun Liu, Yuexian Wu, Xiangdong Cheng","doi":"10.1016/j.ccell.2026.06.015","DOIUrl":"10.1016/j.ccell.2026.06.015","url":null,"abstract":"<p><p>Perioperative immunotherapy improves outcomes in locally advanced gastric or gastroesophageal junction cancer (GC/GEJC), but reliable predictive biomarkers remain elusive. In this biomarker-stratified, randomized, multicenter phase 2 Mountain-02 trail (NCT06374901), 136 patients with operable cT3-4aN + M0 GC/GEJC were enrolled and stratified by tumor-specific MHC class II (tsMHC-II) expression status and then randomized (1:1) to receive perioperative tislelizumab plus chemotherapy or chemotherapy alone. Among tsMHC-II-positive patients, adding tislelizumab to chemotherapy significantly increased the major pathological response (mPR) rate compared with chemotherapy alone (61.8% vs. 26.5%, p = 0.003), meeting the pre-specified primary endpoint. In contrast, no significant benefit was observed in the tsMHC-II-negative subgroup. Within the combination therapy arm, tsMHC-II-positive patients also achieved numerically higher mPR (61.8% vs. 23.5%, p = 0.001) and higher pathological complete response (pCR) rate (32.4% vs. 5.9%, p = 0.006) than tsMHC-II-negative patients. These findings support tsMHC-II as a promising predictive biomarker for perioperative immunotherapy and warrant further validation in larger studies.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1672-1684.e5"},"PeriodicalIF":56.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454747","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 stress-adaptive lipid kinase axis defines metabolic vulnerabilities in neuroendocrine prostate cancer","authors":"Yang Zheng,Caleb Cheng,Yizhi Cao,Gabriel Cruz,Yuping Zhang,Radha Paturu,Somnath Mahapatra,Jing Hu,Rahul Mannan,Hüseyin Karabürk,Rupam Bhattacharyya,Yitong Yin,Yi Zhao,Wenyan Liu,Xuhong Cao,Hui Xue,Chungen Li,Zhen Wang,Stephanie J. Miner,Zachery R. Reichert,Rohit Mehra,Ulka Vaishampayan,Vaibhav Sahai,Lois S. Weisman,Ke Ding,Costas A. Lyssiotis,Yuzhuo Wang,Arul M. Chinnaiyan,Yuanyuan Qiao","doi":"10.1016/j.ccell.2026.07.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2026.07.003","url":null,"abstract":"Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-adaptive lipid kinase axis that supports adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, exacerbates ER stress, and activates a compensatory sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"1 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148665984","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}