Pub Date : 2026-01-12Epub Date: 2025-12-31DOI: 10.1016/j.ccell.2025.12.004
Guanning Wang, Daniel Yoon, Ajeya Nandi, Khushboo Patel, Tarek Azar, Justin Kim, Nicholas A Han, Aaron Nickie, Stella Park, Kevin Wang, Patrick Yan, Shraya Divaker, Jennifer Tabita-Martinez, Lydia Giles, Mary Carberry, Jean Christophe Beltra, Mark M Painter, Cecile Alanio, Ravi K Amaravadi, Lynn M Schuchter, Beatriz M Carreno, Gerald P Linette, David E Elder, Robert M Brody, Phyllis Gimotty, John T Miura, Giorgos C Karakousis, Xiaowei Xu, Tara C Mitchell, Alexander C Huang
Despite widespread immune profiling in cancer immunotherapy, the antigen-specific responses that drive clinical outcomes remain poorly defined. In a prospective neoadjuvant trial (NCT04013854) of a single-dose anti-PD-1 (nivolumab) in stage III melanoma, we performed antigen-specific profiling of melanoma and viral-specific CD8+ T cells across blood, tumor, and lymph node compartments. Using combinatorial tetramers, we detected melanoma-specific CD8+ T cells in 72% of HLA-A1, -A2, and -A3 patients. These cells displayed distinct phenotypes shaped by tissue and antigen context. Tumor-infiltrating T-bet+ intermediate exhausted CD8+ T cells were strongly associated with pathologic response, while CD39+ terminal exhausted cells marked non-response. T-bet and CD39 expression also stratified responses in uninvolved lymph nodes, suggesting early divergence of therapeutic immune trajectories. Longitudinal profiling revealed that circulating melanoma-specific CD8+ T cell dynamics was antigen-dependent and associated with clinical outcomes. Our findings highlight the clinical value of antigen-specific profiling and identify mechanistic correlates of anti-PD-1 efficacy.
{"title":"Antigen-specific profiling identifies T-bet<sup>+</sup> melanoma-specific CD8<sup>+</sup> T cells associated with response to neoadjuvant PD-1 blockade.","authors":"Guanning Wang, Daniel Yoon, Ajeya Nandi, Khushboo Patel, Tarek Azar, Justin Kim, Nicholas A Han, Aaron Nickie, Stella Park, Kevin Wang, Patrick Yan, Shraya Divaker, Jennifer Tabita-Martinez, Lydia Giles, Mary Carberry, Jean Christophe Beltra, Mark M Painter, Cecile Alanio, Ravi K Amaravadi, Lynn M Schuchter, Beatriz M Carreno, Gerald P Linette, David E Elder, Robert M Brody, Phyllis Gimotty, John T Miura, Giorgos C Karakousis, Xiaowei Xu, Tara C Mitchell, Alexander C Huang","doi":"10.1016/j.ccell.2025.12.004","DOIUrl":"10.1016/j.ccell.2025.12.004","url":null,"abstract":"<p><p>Despite widespread immune profiling in cancer immunotherapy, the antigen-specific responses that drive clinical outcomes remain poorly defined. In a prospective neoadjuvant trial (NCT04013854) of a single-dose anti-PD-1 (nivolumab) in stage III melanoma, we performed antigen-specific profiling of melanoma and viral-specific CD8<sup>+</sup> T cells across blood, tumor, and lymph node compartments. Using combinatorial tetramers, we detected melanoma-specific CD8<sup>+</sup> T cells in 72% of HLA-A1, -A2, and -A3 patients. These cells displayed distinct phenotypes shaped by tissue and antigen context. Tumor-infiltrating T-bet<sup>+</sup> intermediate exhausted CD8<sup>+</sup> T cells were strongly associated with pathologic response, while CD39<sup>+</sup> terminal exhausted cells marked non-response. T-bet and CD39 expression also stratified responses in uninvolved lymph nodes, suggesting early divergence of therapeutic immune trajectories. Longitudinal profiling revealed that circulating melanoma-specific CD8<sup>+</sup> T cell dynamics was antigen-dependent and associated with clinical outcomes. Our findings highlight the clinical value of antigen-specific profiling and identify mechanistic correlates of anti-PD-1 efficacy.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"221-234.e5"},"PeriodicalIF":44.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888672","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}
Tertiary lymphoid structures (TLSs) promote antigen-specific anti-tumor immunity, but the regulators of TLSs homeostasis in cancer remain unclear. Using single-cell RNA-sequencing and spatial transcriptomics, we identify an IGLL5+ B cell subset in bladder cancer (BCa). In genetically engineered and humanized mouse models, these IGLL5+ B cells disrupt TLS's integrity and impair immunotherapy responses. Mechanistically, IGLL5+ B cells bind high endothelial venules (HEVs) via IGLL5-LTβR ligand-receptor interactions, with IGLL5 inducing a conformational change in LTβR that inhibits non-canonical NF-κB signaling, leading to TLSs disassembly. Clinically, blocking IGLL5 preserves TLSs and enhances immunotherapy efficacy in patient-derived xenograft (PDX) and pan-cancer models. Our findings suggest that targeting IGLL5+ B cells offers a promising strategy to boost TLS-dependent cancer immunotherapy.
{"title":"B cells disrupt tertiary lymphoid structure formation and suppress anti-tumor immunity.","authors":"Changhao Chen, Mingjie An, Hanhao Zheng, Mingrui Pang, Yuanlong Li, Xiayao Diao, Yuming Luo, Yan Lin, Daiyin Liu, Wenjie Li, Jiancheng Chen, Zhicong Liu, Zewei Chen, Anhong Hu, Wenlong Zhong, Jian Huang, Tianxin Lin","doi":"10.1016/j.ccell.2025.12.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.12.011","url":null,"abstract":"<p><p>Tertiary lymphoid structures (TLSs) promote antigen-specific anti-tumor immunity, but the regulators of TLSs homeostasis in cancer remain unclear. Using single-cell RNA-sequencing and spatial transcriptomics, we identify an IGLL5<sup>+</sup> B cell subset in bladder cancer (BCa). In genetically engineered and humanized mouse models, these IGLL5<sup>+</sup> B cells disrupt TLS's integrity and impair immunotherapy responses. Mechanistically, IGLL5<sup>+</sup> B cells bind high endothelial venules (HEVs) via IGLL5-LTβR ligand-receptor interactions, with IGLL5 inducing a conformational change in LTβR that inhibits non-canonical NF-κB signaling, leading to TLSs disassembly. Clinically, blocking IGLL5 preserves TLSs and enhances immunotherapy efficacy in patient-derived xenograft (PDX) and pan-cancer models. Our findings suggest that targeting IGLL5<sup>+</sup> B cells offers a promising strategy to boost TLS-dependent cancer immunotherapy.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":""},"PeriodicalIF":44.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942174","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}
Pub Date : 2026-01-08DOI: 10.1016/j.ccell.2025.12.014
Zile Fu, Yuanli Song, Fen Liu, Lv Chen, Shangli Cai, Peng Cui, Guoqiang Wang, Wenchuan Xie, Shu Zhang, Li Ding, Pei Wang, Bing Zhang, Henry Rodriguez, Feiling Feng, Xufeng Zhang, Wei Gong, Qiang Gao, Daming Gao, Hu Zhou, Jia Fan
Gallbladder cancer (GBC) is a highly aggressive malignancy with dismal outcomes. To dissect its molecular characteristics and identify potential therapeutic avenues, we performed proteogenomic characterization of 195 tumors and 135 adjacent non-cancerous gallbladder tissues. Integrative analyses highlighted TP53 and ELF3 mutations as key drivers disrupting signaling and metabolism. ErbB2 amplification, a pivotal genomic event, was associated with reduced canonical PI3K/AKT and RAS/MAPK/ERK signaling yet enhanced proliferative activity. We discovered potential gain-of-function mutations in ErbB2 and ErbB3 predicted to enhance ErbB2-ErbB3 heterodimer activity. ACAT1 and PHGDH were identified as metabolic drivers of GBC liver invasion. Integrated molecular and immune subtyping delineated four distinct multi-omics and immune microenvironment subtypes, each carrying prognostic and therapeutic relevance. Although rare, neuroendocrine GBC was separately characterized, revealing MEIS1 as a potential regulator of neuroendocrine-like features. Together, this study establishes a proteogenomic landscape of GBC, providing biological insights and guiding future translational efforts.
{"title":"Integrative proteogenomic analysis provides molecular insights and clinical significance in gallbladder cancer","authors":"Zile Fu, Yuanli Song, Fen Liu, Lv Chen, Shangli Cai, Peng Cui, Guoqiang Wang, Wenchuan Xie, Shu Zhang, Li Ding, Pei Wang, Bing Zhang, Henry Rodriguez, Feiling Feng, Xufeng Zhang, Wei Gong, Qiang Gao, Daming Gao, Hu Zhou, Jia Fan","doi":"10.1016/j.ccell.2025.12.014","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.12.014","url":null,"abstract":"Gallbladder cancer (GBC) is a highly aggressive malignancy with dismal outcomes. To dissect its molecular characteristics and identify potential therapeutic avenues, we performed proteogenomic characterization of 195 tumors and 135 adjacent non-cancerous gallbladder tissues. Integrative analyses highlighted <em>TP53</em> and <em>ELF3</em> mutations as key drivers disrupting signaling and metabolism. <em>ErbB2</em> amplification, a pivotal genomic event, was associated with reduced canonical PI3K/AKT and RAS/MAPK/ERK signaling yet enhanced proliferative activity. We discovered potential gain-of-function mutations in <em>ErbB2</em> and <em>ErbB3</em> predicted to enhance ErbB2-ErbB3 heterodimer activity. ACAT1 and PHGDH were identified as metabolic drivers of GBC liver invasion. Integrated molecular and immune subtyping delineated four distinct multi-omics and immune microenvironment subtypes, each carrying prognostic and therapeutic relevance. Although rare, neuroendocrine GBC was separately characterized, revealing MEIS1 as a potential regulator of neuroendocrine-like features. Together, this study establishes a proteogenomic landscape of GBC, providing biological insights and guiding future translational efforts.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"15 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937526","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}
Pub Date : 2026-01-08DOI: 10.1016/j.ccell.2025.12.008
Andrea H. Bild, Michelle C. Sangar, Jasmine A. McQuerry, Trey Ideker, Scott Kopetz, Lisa Carey, Aritro Nath, Daniel Marcus, Allison Regier, Naim Rashid, Regina Barzilay, Eric Winer, Ravi Salgia, Jyoti Malhotra, Andrew Gentles, Kenneth Buetow, Faisal Mahmood, David W. Markman, James A. Eddy, Ying Yuan
ADAPT is a nationwide initiative to transform cancer care by detecting and responding to tumor evolution in real time. Integrating multimodal data, interpretable AI, and an evolutionary clinical trial platform, ADAPT predicts emerging resistance traits and guides treatment adjustments as tumors change. A unified national infrastructure enables continuous learning across patients, linking discovery directly to care. By making therapy responsive to tumor changes, ADAPT delivers a scalable model designed to improve outcomes in precision oncology.
{"title":"The ADAPT learning cancer treatment system: ARPA-H’s initiative to revolutionize cancer therapy","authors":"Andrea H. Bild, Michelle C. Sangar, Jasmine A. McQuerry, Trey Ideker, Scott Kopetz, Lisa Carey, Aritro Nath, Daniel Marcus, Allison Regier, Naim Rashid, Regina Barzilay, Eric Winer, Ravi Salgia, Jyoti Malhotra, Andrew Gentles, Kenneth Buetow, Faisal Mahmood, David W. Markman, James A. Eddy, Ying Yuan","doi":"10.1016/j.ccell.2025.12.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.12.008","url":null,"abstract":"ADAPT is a nationwide initiative to transform cancer care by detecting and responding to tumor evolution in real time. Integrating multimodal data, interpretable AI, and an evolutionary clinical trial platform, ADAPT predicts emerging resistance traits and guides treatment adjustments as tumors change. A unified national infrastructure enables continuous learning across patients, linking discovery directly to care. By making therapy responsive to tumor changes, ADAPT delivers a scalable model designed to improve outcomes in precision oncology.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"47 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937996","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}
Pub Date : 2026-01-08DOI: 10.1016/j.ccell.2025.12.016
Salvador Alonso, Kanwal Raghav, Van K Morris, Kristin Alfaro-Munoz, Tanios Bekaii-Saab, Timothy L Cannon, Ryan B Corcoran, Nicholas Duesbery, Manju George, David Hsu, Christopher Lieu, Anirban Maitra, Dipen Maru, Jasmine A McQuerry, David Menter, Jonathan Mizrahi, Kimmie Ng, Aparna Parikh, Kunal Rai, Michelle C Sangar, Kenna R Shaw, John Paul Shen, John H Strickler, Ann D Feehan, Alda L Tam, Guglielmo Vetere, Rona Yaeger, Ying Yuan, Xiling Shen, Andrea H Bild, Scott Kopetz
Cancer evolution is a complex and dynamic process, yet most treatment strategies remain static. Infrequent tumor sampling has limited our ability to counteract the transient adaptive states that precede resistance. To address this gap, ARPA-H launched the ADAPT program, an initiative aimed at transforming cancer care by aligning therapies with real-time tumor evolution. Within this framework, the ASCEND-CRC trial aims to uncover early adaptive mechanisms and identify biomarkers to guide therapeutic decision-making in metastatic colorectal cancer (CRC). The study moves beyond single pre-treatment biomarkers by integrating multimodal profiling to longitudinally track tumor evolution and define an actionable set of dynamic biomarkers that inform treatment decisions. Together with other ADAPT initiatives, ASCEND-CRC represents a paradigm shift in precision oncology, establishing a scalable platform to intercept resistance.
{"title":"Framework for cancer evolution profiling and interception in colorectal cancer: ASCEND-CRC program.","authors":"Salvador Alonso, Kanwal Raghav, Van K Morris, Kristin Alfaro-Munoz, Tanios Bekaii-Saab, Timothy L Cannon, Ryan B Corcoran, Nicholas Duesbery, Manju George, David Hsu, Christopher Lieu, Anirban Maitra, Dipen Maru, Jasmine A McQuerry, David Menter, Jonathan Mizrahi, Kimmie Ng, Aparna Parikh, Kunal Rai, Michelle C Sangar, Kenna R Shaw, John Paul Shen, John H Strickler, Ann D Feehan, Alda L Tam, Guglielmo Vetere, Rona Yaeger, Ying Yuan, Xiling Shen, Andrea H Bild, Scott Kopetz","doi":"10.1016/j.ccell.2025.12.016","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.12.016","url":null,"abstract":"<p><p>Cancer evolution is a complex and dynamic process, yet most treatment strategies remain static. Infrequent tumor sampling has limited our ability to counteract the transient adaptive states that precede resistance. To address this gap, ARPA-H launched the ADAPT program, an initiative aimed at transforming cancer care by aligning therapies with real-time tumor evolution. Within this framework, the ASCEND-CRC trial aims to uncover early adaptive mechanisms and identify biomarkers to guide therapeutic decision-making in metastatic colorectal cancer (CRC). The study moves beyond single pre-treatment biomarkers by integrating multimodal profiling to longitudinally track tumor evolution and define an actionable set of dynamic biomarkers that inform treatment decisions. Together with other ADAPT initiatives, ASCEND-CRC represents a paradigm shift in precision oncology, establishing a scalable platform to intercept resistance.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":""},"PeriodicalIF":44.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942193","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}
Pub Date : 2025-12-24DOI: 10.1016/j.ccell.2025.12.002
Caroline G. Fahey, Anthony F. Cordova, Patrick C. Gedeon, David A. Barbie
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway bridges cytosolic DNA sensing with type I interferon activation in cancer. Despite promising preclinical results, generating clinically meaningful anti-tumor immunity with STING agonists has faced substantial challenges, highlighting gaps in model systems and the biologic complexity of STING signaling. In the tumor microenvironment (TME), STING activation elicits highly context- and cell type-dependent outcomes, with divergent effects on tumor cells, myeloid cells, T cells, and other cell types. Furthermore, the downstream induction of type I interferon and other cytokines in the TME can have both pro- and anti-tumorigenic consequences, with emerging interferon-independent functions of STING signaling adding further complexity. In this review, we chart the diverse impact of STING activation across the TME and discuss how recent insights can inform the design of next-generation therapeutic strategies that more effectively harness STING-driven innate immunity to promote durable anti-tumor activity in humans.
{"title":"Targeting STING to generate therapeutic anti-tumor immunity","authors":"Caroline G. Fahey, Anthony F. Cordova, Patrick C. Gedeon, David A. Barbie","doi":"10.1016/j.ccell.2025.12.002","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.12.002","url":null,"abstract":"The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway bridges cytosolic DNA sensing with type I interferon activation in cancer. Despite promising preclinical results, generating clinically meaningful anti-tumor immunity with STING agonists has faced substantial challenges, highlighting gaps in model systems and the biologic complexity of STING signaling. In the tumor microenvironment (TME), STING activation elicits highly context- and cell type-dependent outcomes, with divergent effects on tumor cells, myeloid cells, T cells, and other cell types. Furthermore, the downstream induction of type I interferon and other cytokines in the TME can have both pro- and anti-tumorigenic consequences, with emerging interferon-independent functions of STING signaling adding further complexity. In this review, we chart the diverse impact of STING activation across the TME and discuss how recent insights can inform the design of next-generation therapeutic strategies that more effectively harness STING-driven innate immunity to promote durable anti-tumor activity in humans.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"29 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813721","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}
Pub Date : 2025-12-19DOI: 10.1016/j.ccell.2025.11.011
Harold N. Tan, Mitchell J. Elliott, Ian M. Silverman, Lillian L. Siu, Timothy A. Yap
{"title":"Circulating tumor DNA as a biomarker in early phase clinical trials","authors":"Harold N. Tan, Mitchell J. Elliott, Ian M. Silverman, Lillian L. Siu, Timothy A. Yap","doi":"10.1016/j.ccell.2025.11.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.11.011","url":null,"abstract":"","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"7 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786042","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}
Pub Date : 2025-12-11DOI: 10.1016/j.ccell.2025.11.006
Hadeesha Piyadasa, Benjamin Oberlton, Mikaela Ribi, Ke Leow, Jolene S. Ranek, Inna Averbukh, Meelad Amouzgar, Candace C. Liu, Davide G. Franchina, Noah F. Greenwald, Erin F. McCaffrey, Rashmi Kumar, Selena Ferrian, Albert G. Tsai, Ferda Filiz, Christine Camacho Fullaway, Marc Bosse, Sricharan Reddy Varra, Alex Kong, Cameron Sowers, Michael Angelo
Gliomas are among the most lethal cancers, with limited treatment options. To uncover hallmarks of therapeutic escape and tumor microenvironment (TME) landscape, we applied spatial proteomics, transcriptomics, and glycomics to 670 lesions from 310 adult and pediatric patients. Single-cell analysis shows high B7H3+ tumor cell prevalence in glioblastoma (GBM) and pleomorphic xanthoastrocytoma, while most gliomas, including pediatric cases, express targetable tumor antigens in less than 50% of tumor cells, potentially explaining trial failures. Paired samples of isocitrate dehydrogenase (IDH)-mutant gliomas reveal recurrence driven by tumor-immune spatial reorganization, shifting from T cell and vasculature-associated myeloid cell-enriched niches to microglia and CD206+ macrophage-dominated tumors. Multi-omic integration identified N-glycosylation as the best classifier of grade, while the immune transcriptome best predicted GBM survival. Provided as a community resource, this study offers a framework for glioma targeting, classification, outcome prediction, and a baseline of TME composition across all stages.
{"title":"Multi-omic landscape of human gliomas from diagnosis to treatment and recurrence","authors":"Hadeesha Piyadasa, Benjamin Oberlton, Mikaela Ribi, Ke Leow, Jolene S. Ranek, Inna Averbukh, Meelad Amouzgar, Candace C. Liu, Davide G. Franchina, Noah F. Greenwald, Erin F. McCaffrey, Rashmi Kumar, Selena Ferrian, Albert G. Tsai, Ferda Filiz, Christine Camacho Fullaway, Marc Bosse, Sricharan Reddy Varra, Alex Kong, Cameron Sowers, Michael Angelo","doi":"10.1016/j.ccell.2025.11.006","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.11.006","url":null,"abstract":"Gliomas are among the most lethal cancers, with limited treatment options. To uncover hallmarks of therapeutic escape and tumor microenvironment (TME) landscape, we applied spatial proteomics, transcriptomics, and glycomics to 670 lesions from 310 adult and pediatric patients. Single-cell analysis shows high B7H3+ tumor cell prevalence in glioblastoma (GBM) and pleomorphic xanthoastrocytoma, while most gliomas, including pediatric cases, express targetable tumor antigens in less than 50% of tumor cells, potentially explaining trial failures. Paired samples of isocitrate dehydrogenase (IDH)-mutant gliomas reveal recurrence driven by tumor-immune spatial reorganization, shifting from T cell and vasculature-associated myeloid cell-enriched niches to microglia and CD206<sup>+</sup> macrophage-dominated tumors. Multi-omic integration identified N-glycosylation as the best classifier of grade, while the immune transcriptome best predicted GBM survival. Provided as a community resource, this study offers a framework for glioma targeting, classification, outcome prediction, and a baseline of TME composition across all stages.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"19 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717908","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}
Pub Date : 2025-12-11DOI: 10.1016/j.ccell.2025.11.010
Ankur Sharma, Mehak Gupta, Jacob George, Florent Ginhoux
{"title":"Oncofetal reprogramming of malignant seeds and their ecosystem: Implications in clinical research","authors":"Ankur Sharma, Mehak Gupta, Jacob George, Florent Ginhoux","doi":"10.1016/j.ccell.2025.11.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.11.010","url":null,"abstract":"","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"19 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731566","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}
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