Cancer CellPub Date : 2025-06-26DOI: 10.1016/j.ccell.2025.05.017
Fan Huang, Zengli Liu, Yan Song, Ganyu Wang, Anda Shi, Tianli Chen, Shaohui Huang, Shuo Lian, Kangshuai Li, Yongchang Tang, Lijie Zheng, Guoli Sheng, Nuoqi Zhang, Fan Yang, Chang Pan, Weiqiang Jing, Zongli Zhang, Yunfei Xu
{"title":"Bile acids activate cancer-associated fibroblasts and induce an immunosuppressive microenvironment in cholangiocarcinoma","authors":"Fan Huang, Zengli Liu, Yan Song, Ganyu Wang, Anda Shi, Tianli Chen, Shaohui Huang, Shuo Lian, Kangshuai Li, Yongchang Tang, Lijie Zheng, Guoli Sheng, Nuoqi Zhang, Fan Yang, Chang Pan, Weiqiang Jing, Zongli Zhang, Yunfei Xu","doi":"10.1016/j.ccell.2025.05.017","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.017","url":null,"abstract":"Cholangiocarcinoma (CCA) is a highly lethal malignancy originating from the biliary tract and characterized with exposure to high levels of bile acids (BAs). Immunotherapies have demonstrated limited efficacy in CCA, but the underlying mechanism remains elusive. In this study, we reveal that the excessive BAs specifically activate GPBAR1 on cancer-associated fibroblasts (CAFs) to express high levels of CXCL10, enhancing epithelial-mesenchymal transition (EMT) and metastasis of CCA cells and creating an immunosuppressive tumor microenvironment (TME) by recruiting neutrophils in CCA. Interestingly, single-cell RNA sequencing analysis demonstrates that CAFs in CCA, but not other cancer types examined, specifically express GPBAR1, a receptor for BAs. GPBAR1-CXCL10 axis inhibition enhances the efficacy of pembrolizumab in multiple CCA preclinical models. High BA levels and upregulated GPBAR1 expression predict poor prognosis and inferior immunotherapy response. In summary, our study reveals an immunosuppressive mechanism of BAs and identifies GPBAR1 and CXCL10 as potential immunotherapeutic targets in CCA.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"8 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488374","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}
Cancer CellPub Date : 2025-06-26DOI: 10.1016/j.ccell.2025.06.003
John M. Warrington, Nathan Singh
{"title":"Disarming myeloid resistance in CAR T therapy","authors":"John M. Warrington, Nathan Singh","doi":"10.1016/j.ccell.2025.06.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.003","url":null,"abstract":"Uncovering mechanisms of resistance to chimeric antigen receptor (CAR) T cell therapy for B cell lymphoma is of paramount importance. In this issue of <em>Cancer Cell</em>, Stahl et al. identify a CSF1R<sup>+</sup> myelo-monocytic population that disrupts CAR T cell function and show that inhibition of CSF1R enhances efficacy of CD19-targeted CAR T cells.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"95 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488360","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}
Cancer CellPub Date : 2025-06-19DOI: 10.1016/j.ccell.2025.05.016
Lyla J. Stanland, Hayden P. Huggins, Snehasudha S. Sahoo, Alessandro Porrello, Yogitha Chareddy, Salma H. Azam, Jillian L. Perry, Pradeep S. Pallan, Kristina Whately, Lincy Edatt, William D. Green, Matthew C. Fleming, Jonah Im, Christina Gutierrez-Ford, Imani Simmons, Alyaa Dawoud, Katherine I. Zhou, Vandanaa Jayaprakash, Rani S. Sellers, Gabriela de la Cruz, Chad V. Pecot
{"title":"A first-in-class EGFR-directed KRAS G12V selective inhibitor","authors":"Lyla J. Stanland, Hayden P. Huggins, Snehasudha S. Sahoo, Alessandro Porrello, Yogitha Chareddy, Salma H. Azam, Jillian L. Perry, Pradeep S. Pallan, Kristina Whately, Lincy Edatt, William D. Green, Matthew C. Fleming, Jonah Im, Christina Gutierrez-Ford, Imani Simmons, Alyaa Dawoud, Katherine I. Zhou, Vandanaa Jayaprakash, Rani S. Sellers, Gabriela de la Cruz, Chad V. Pecot","doi":"10.1016/j.ccell.2025.05.016","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.016","url":null,"abstract":"Despite <em>KRAS</em><sup><em>G12V</em></sup> being the second most common <em>KRAS</em> mutation in cancer, no direct inhibitors targeting KRAS<sup>G12V</sup> have been approved. RNA interference (RNAi) has faced numerous obstacles as cancer therapeutic, including the lack of cancer-specific tissue targeting, rapid oligonucleotide nuclease degradation, and clearance from circulation. Recently, the use of targetable ligands conjugated to chemically modified siRNAs have shown remarkable promise in circumventing these barriers. In this study, we demonstrate that an EGFR-directed RNAi molecule (EFTX-G12V) is highly selective for <em>KRAS</em><sup><em>G12V</em></sup> and exhibits improved therapeutic activity over pan-KRAS targeting, including enhanced inhibition of several cancer hallmarks. Using a targeted RNAi delivery platform, we achieve effective tumor silencing of <em>KRAS</em><sup><em>G12V</em></sup> and significant anti-tumor activity across several cancer models. Our findings represent a technological advance in oncogene targeting using RNAi and provide new biologic insights in KRAS targeting with potential implications for safety and efficacy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"29 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319500","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}
Cancer CellPub Date : 2025-06-19DOI: 10.1016/j.ccell.2025.06.001
Nick Li, Christopher M. Jones, Jayant K. Rane, Christopher J. Tape, Maria A. Hawkins
{"title":"Biomimetic models in radiotherapy research: An essential bridge between bench and beam","authors":"Nick Li, Christopher M. Jones, Jayant K. Rane, Christopher J. Tape, Maria A. Hawkins","doi":"10.1016/j.ccell.2025.06.001","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.001","url":null,"abstract":"Biomimetic <em>in vitro</em> models that more accurately replicate tumor and microenvironmental complexity are transforming radiotherapy research. Unlike traditional 2D cell lines, 3D models such as organoids and organ-on-chips capture key determinants of radiation sensitivity and resistance, improving translational relevance. Broader adoption of these systems promises to bridge the gap between laboratory research and clinical radiotherapy, enabling more effective biomarker discovery and therapeutic innovation.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"60 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319503","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}
Cancer CellPub Date : 2025-06-18DOI: 10.1016/j.ccell.2025.06.002
Xubin Li, Kartik Singhal, Qing Deng, Dai Chihara, David Russler-Germain, R. Andrew Harkins, Jared Henderson, Kotaro Arita, Atish Kizhakeyil, Ryan Sun, Priya Lakra, Usama Hussein, Jennifer A. Foltz, Ashley Wilson, Evelyn Schmidt, Imran Nizamuddin, Tommy Dinh, Akhil Kesaraju, Mark P. Hamilton, Carl Allen, Michael R. Green
{"title":"Large B cell lymphoma microenvironment archetype profiles","authors":"Xubin Li, Kartik Singhal, Qing Deng, Dai Chihara, David Russler-Germain, R. Andrew Harkins, Jared Henderson, Kotaro Arita, Atish Kizhakeyil, Ryan Sun, Priya Lakra, Usama Hussein, Jennifer A. Foltz, Ashley Wilson, Evelyn Schmidt, Imran Nizamuddin, Tommy Dinh, Akhil Kesaraju, Mark P. Hamilton, Carl Allen, Michael R. Green","doi":"10.1016/j.ccell.2025.06.002","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.06.002","url":null,"abstract":"Large B cell lymphomas (LBCL) are clinically and biologically heterogeneous lymphoid malignancies with complex microenvironments that are central to disease etiology. Here, we have employed single-nucleus multiome profiling of 232 tumor and control biopsies to characterize diverse cell types and subsets that are present in LBCL tumors, effectively capturing the lymphoid, myeloid, and non-hematopoietic cell compartments. Cell subsets co-occurred in stereotypical lymphoma microenvironment archetype profiles (LymphoMAPs) defined by; (1) a sparsity of T cells and high frequencies of cancer-associated fibroblasts and tumor-associated macrophages (FMAC); (2) lymph node architectural cell types with naive and memory T cells (LN); or (3) activated macrophages and exhausted CD8<sup>+</sup> T cells (TEX). Divergent patterns of cell-cell communication underpinned the transcriptional phenotypes of archetype-defining cell subsets resulting in exclusion, support, or suppression of T cells, respectively. Consistent with this, LymphoMAPs were associated with significantly different clinical outcomes following CD19 chimeric antigen receptor (CAR) T cell therapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"6 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144312026","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}
Cancer CellPub Date : 2025-06-12DOI: 10.1016/j.ccell.2025.05.012
Yang Du, Jianmin Wu
{"title":"A unified pan-cancer proteome atlas","authors":"Yang Du, Jianmin Wu","doi":"10.1016/j.ccell.2025.05.012","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.012","url":null,"abstract":"In this issue of <em>Cancer Cell</em>, Knol et al. present the Pan-Cancer Proteome Atlas (TPCPA), a proteomic resource developed using single-shot data-independent acquisition mass spectrometry (DIA-MS). TPCPA provides proteome-scale quantifications of 999 tumors across 22 cancer types in a unified manner, for discovering tumor biology, biomarkers, and therapeutic targets.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"6 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269105","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}
Cancer CellPub Date : 2025-06-12DOI: 10.1016/j.ccell.2025.05.015
Manuel Colucci, Miles Sarill, Martino Maddalena, Aurora Valdata, Martina Troiani, Martina Massarotti, Marco Bolis, Silvia Bressan, Anna Kohl, Daniele Robesti, Miriam Saponaro, Qiu Shi, Pan Song, Daniela Brina, Bianca Calì, Andrea Alimonti
{"title":"Senescence in cancer","authors":"Manuel Colucci, Miles Sarill, Martino Maddalena, Aurora Valdata, Martina Troiani, Martina Massarotti, Marco Bolis, Silvia Bressan, Anna Kohl, Daniele Robesti, Miriam Saponaro, Qiu Shi, Pan Song, Daniela Brina, Bianca Calì, Andrea Alimonti","doi":"10.1016/j.ccell.2025.05.015","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.015","url":null,"abstract":"Cellular senescence is a state of stable cell-cycle arrest induced by various intrinsic and extrinsic stressors, serving as a protective mechanism to prevent the proliferation of damaged cells. While this process is crucial for tissue homeostasis and tumor suppression, the progressive accumulation of senescent cells (SnCs) over time is implicated in age-related pathologies, including immune dysfunction and cancer. In oncology, senescence plays a paradoxical role: it can inhibit tumor development by halting the growth of potentially malignant cells, yet it may also facilitate tumor progression through the senescence-associated secretory phenotype (SASP). This review explores the defining features of senescence in cancer, its complex interactions with tumor cells, the stroma, and the immune system, and its context-dependent outcomes. We also discuss current and emerging therapeutic strategies that target SnCs—either by inducing or eliminating them—as well as AI-driven approaches for their detection and characterization in cancer.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"6 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269116","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}
Cancer CellPub Date : 2025-06-12DOI: 10.1016/j.ccell.2025.05.004
Ye He, Hao-Xiang Wu, Feng Wang
{"title":"Drug-induced mismatch repair deficiency: Mixed prospects","authors":"Ye He, Hao-Xiang Wu, Feng Wang","doi":"10.1016/j.ccell.2025.05.004","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.004","url":null,"abstract":"Most metastatic colorectal cancer (CRC) is mismatch repair proficient (pMMR) with low immunogenicity. In this issue of <em>Cancer Cell</em>, Vitiello et al. and Rousseau et al. reveal that temozolomide-cisplatin combinations induce mismatch repair-deficient-like phenotypes and reshape the tumor microenvironment in preclinical pMMR CRC models, yet the clinical trial calls for further optimization.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"8 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269117","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}
Cancer CellPub Date : 2025-06-12DOI: 10.1016/j.ccell.2025.05.011
Iva Nikolic, Joseph Cursons, Benjamin Shields, Stephane Chappaz, Harrison Sudholz, Xiangpeng Meng, Patrick Constantinescu, Reshma Vijayakumaran, Michael D’Angelo, Momeneh Foroutan, David Ladd, Matthew Veldman, Jason Glab, Tahlia Procter, Hae-Young Park, Julian Contet, Felix Deuss, Kahlia Wong, Yi Sun, Richard Berry, Nicholas D. Huntington
{"title":"Enhancing anti-tumor immunity of natural killer cells through targeting IL-15R signaling","authors":"Iva Nikolic, Joseph Cursons, Benjamin Shields, Stephane Chappaz, Harrison Sudholz, Xiangpeng Meng, Patrick Constantinescu, Reshma Vijayakumaran, Michael D’Angelo, Momeneh Foroutan, David Ladd, Matthew Veldman, Jason Glab, Tahlia Procter, Hae-Young Park, Julian Contet, Felix Deuss, Kahlia Wong, Yi Sun, Richard Berry, Nicholas D. Huntington","doi":"10.1016/j.ccell.2025.05.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.011","url":null,"abstract":"Interleukin-15 receptor (IL-15R) agonists induce anti-tumor immunity in pre-clinical models. However, dose-limiting toxicity has hampered their clinical development. We performed genome-wide CRISPR screens to reveal the complete IL-15R signaling mechanism in natural killer (NK) cells and discovered that ubiquitin-dependent IL-15R degradation is the dominant mechanism restraining IL-15R signaling. Key hits included the NEDD8 E2-conjugating enzyme UBE2F, the ubiquitin E3-ligase ARIH2, and Cullin-5 RING E3 ligase (CRL5) members. We found that UBE2F was required for neddylation and activation of CUL5, whereas ARIH2 contributed to CRL5-mediated IL-15RB degradation. Ablation of <em>ARIH2</em> or <em>UBE2F</em> increased IL-15RB surface expression and enhanced signaling, resulting in proinflammatory cytokine production and augmented natural and CAR-mediated cytotoxicity. In mice lacking <em>Arih2</em>, <em>Rnf7</em>, or <em>Ube2f</em>, we observed that the IL-15R hyperresponsive NK cells exhibited superior <em>in vivo</em> anti-tumor immunity against primary and disseminated metastatic tumors. Thus, we have identified the enzymes UBE2F and ARIH2 as tractable immunotherapy drug targets.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"22 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268963","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}
Cancer CellPub Date : 2025-06-12DOI: 10.1016/j.ccell.2025.05.014
Pietro Paolo Vitiello, Benoit Rousseau, Rosaria Chilà, Paolo Battuello, Vito Amodio, Vittorio Battaglieri, Gaia Grasso, Sharon Scardellato, Achille Anselmo, Francesca Clemente, Giuseppe Rospo, Simona Lamba, Alice Bartolini, Federica Pisati, Claudio Tripodo, Noemi Congiusta, Mariangela Russo, Giovanni Crisafulli, Federica Di Nicolantonio, Giovanni Germano, Alberto Bardelli
{"title":"Cisplatin and temozolomide combinatorial treatment triggers hypermutability and immune surveillance in experimental cancer models","authors":"Pietro Paolo Vitiello, Benoit Rousseau, Rosaria Chilà, Paolo Battuello, Vito Amodio, Vittorio Battaglieri, Gaia Grasso, Sharon Scardellato, Achille Anselmo, Francesca Clemente, Giuseppe Rospo, Simona Lamba, Alice Bartolini, Federica Pisati, Claudio Tripodo, Noemi Congiusta, Mariangela Russo, Giovanni Crisafulli, Federica Di Nicolantonio, Giovanni Germano, Alberto Bardelli","doi":"10.1016/j.ccell.2025.05.014","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.014","url":null,"abstract":"Hypermutation induced by mismatch repair (MMR) inactivation leads to immune surveillance in colorectal cancer (CRC) and in several other malignancies. We investigated the impact of a rationally designed chemotherapy combination on the generation of hypermutation and immunogenicity in otherwise immune-refractory CRC and breast cancer mouse models. Combinatorial treatment with cisplatin (CDDP) and temozolomide (TMZ) induces an adaptive downregulation of MMR, resulting in chemotherapy-dependent hypermutability and increase in predicted neoantigens. This combination specifically alters the immune fitness of the tumors, ultimately leading to CD8<sup>+</sup> T cell-mediated immune surveillance, immunoediting of chemotherapy-induced neoantigens, and durable immunological memory. Treatment with CDDP and TMZ also remodels the innate immune microenvironment and induces long-lasting responses and complete rejections when combined with anti-PD-1 therapy in mice. The same effects are not observed using the clinically approved combination of 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI). Treatment-induced hypermutation can enhance anti-tumor immune responses, offering additional avenues for cancer treatment.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"23 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268965","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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