Cancer CellPub Date : 2025-02-27DOI: 10.1016/j.ccell.2025.02.003
Susanne Müller, Domenico Sanfelice, Paul Workman
{"title":"Probing cancer with small-molecule tools—Progress and challenges","authors":"Susanne Müller, Domenico Sanfelice, Paul Workman","doi":"10.1016/j.ccell.2025.02.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.003","url":null,"abstract":"Chemical probes are powerful small-molecule tools in fundamental and translational cancer research. They are highly versatile, complementing genetic technologies in the annotation of protein function, and invaluable in target validation and drug discovery. However, continued improvements are needed to enhance best practices in selection and use of chemical probes. We discuss progress over the last decade, highlight key issues, and indicate a path to generate a high-quality chemical probe for every human protein.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"32 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506860","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":"Global alliances in translational cancer research","authors":"Hui-Yan Luo, Yun-Xin Lu, Kohei Shitara, Heinz-Josef Lenz, Rui-Hua Xu","doi":"10.1016/j.ccell.2025.02.005","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.005","url":null,"abstract":"Translating basic cancer biology into effective clinical therapies remains a major challenge due to differences in research models, communication gaps, and limited funding. This commentary underscores the transformative potential of international collaborations, which integrate diverse resources, multidisciplinary talents, and innovative trial designs to bridge the gap between laboratory discoveries and clinical applications. By fostering global alliances, sharing knowledge, and harmonizing regulatory and funding frameworks, we can accelerate breakthroughs in cancer treatment, improving patient outcomes worldwide.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"27 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506855","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 : 2025-02-27DOI: 10.1016/j.ccell.2025.02.004
Tanya Schild, Patrick Wallisch, Yixuan Zhao, Ya-Ting Wang, Lyric Haughton, Rachel Chirayil, Kaitlyn Pierpont, Kevin Chen, Sara Nunes-Violante, Justin Cross, Elisa de Stanchina, Craig B. Thompson, David A. Scheinberg, Justin S.A. Perry, Kayvan R. Keshari
{"title":"Metabolic engineering to facilitate anti-tumor immunity","authors":"Tanya Schild, Patrick Wallisch, Yixuan Zhao, Ya-Ting Wang, Lyric Haughton, Rachel Chirayil, Kaitlyn Pierpont, Kevin Chen, Sara Nunes-Violante, Justin Cross, Elisa de Stanchina, Craig B. Thompson, David A. Scheinberg, Justin S.A. Perry, Kayvan R. Keshari","doi":"10.1016/j.ccell.2025.02.004","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.004","url":null,"abstract":"Fructose consumption is elevated in western diets, but its impact on anti-tumor immunity is unclear. Fructose is metabolized in the liver and small intestine, where fructose transporters are highly expressed. Most tumors are unable to drive glycolytic flux using fructose, enriching fructose in the tumor microenvironment (TME). Excess fructose in the TME may be utilized by immune cells to enhance effector functions if engineered to express the fructose-specific transporter GLUT5. Here, we show that GLUT5-expressing CD8<sup>+</sup> T cells, macrophages, and chimeric antigen receptor (CAR) T cells all demonstrate improved effector functions in glucose-limited conditions <em>in vitro</em>. GLUT5-expressing T cells show high fructolytic activity <em>in vitro and</em> higher anti-tumor efficacy in murine syngeneic and human xenograft models <em>in vivo</em>, especially following fructose supplementation. Together, our data demonstrates that metabolic engineering through GLUT5 enables immune cells to efficiently utilize fructose and boosts anti-tumor immunity in the glucose-limited TME.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"66 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506857","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 : 2025-02-27DOI: 10.1016/j.ccell.2025.02.001
Simone Lubrano, Rodolfo Daniel Cervantes-Villagrana, Farhoud Faraji, Sydney Ramirez, Kuniaki Sato, Sendi R. Adame-Garcia, Adam Officer, Nadia Arang, Damiano C. Rigiracciolo, Paola Y. Anguiano Quiroz, Claudia Martini, YiYu Wang, Fleur M. Ferguson, Antonietta Bacchiocchi, Ruth Halaban, Silvia Coma, Sheri L. Holmen, Jonathan A. Pachter, Andrew E. Aplin, J. Silvio Gutkind
{"title":"FAK inhibition combined with the RAF-MEK clamp avutometinib overcomes resistance to targeted and immune therapies in BRAF V600E melanoma","authors":"Simone Lubrano, Rodolfo Daniel Cervantes-Villagrana, Farhoud Faraji, Sydney Ramirez, Kuniaki Sato, Sendi R. Adame-Garcia, Adam Officer, Nadia Arang, Damiano C. Rigiracciolo, Paola Y. Anguiano Quiroz, Claudia Martini, YiYu Wang, Fleur M. Ferguson, Antonietta Bacchiocchi, Ruth Halaban, Silvia Coma, Sheri L. Holmen, Jonathan A. Pachter, Andrew E. Aplin, J. Silvio Gutkind","doi":"10.1016/j.ccell.2025.02.001","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.02.001","url":null,"abstract":"Widespread <em>BRAF</em> mutations result in persistent RAS-RAF-MEK-ERK (MAPK) signaling in melanoma. BRAF (BRAFi) and MEK (MEKi) inhibitors are approved for <em>BRAF</em> V600E melanomas, including those progressing on immunotherapy; however, rapid resistance to these agents highlights the need for novel strategies. Here, transcriptome analysis of <em>BRAF</em> V600E melanomas from patients resistant to BRAFi and MEKi shows activation of focal adhesion signaling. Consistently, BRAFi, MEKi, and the RAF-MEK clamp avutometinib activate focal adhesion kinase (FAK) in melanoma cells. Mechanistically, inhibition of an MAPK-RhoE (RND3) feedback loop results in the adaptive activation of RhoA-FAK-AKT. In turn, FAK inhibitors (FAKi) exert potent pro-apoptotic activity when combined with MAPK pathway inhibition. FAKi plus avutometinib overcomes resistance in multiple models derived from BRAFi plus MEKi-resistant melanoma patients and immunotherapy-resistant syngeneic mouse models. These findings provide a rationale for the development of avutometinib in combination with FAKi for patients with <em>BRAF</em> V600E melanoma progressing on BRAFi plus MEKi or immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"26 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506859","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 : 2025-02-20DOI: 10.1016/j.ccell.2025.01.013
Patrizia Porazzi, Siena Nason, Ziqi Yang, Alberto Carturan, Guido Ghilardi, Puneeth Guruprasad, Ruchi P. Patel, Melody Tan, Anushka Anant Padmanabhan, Jean Lemoine, Eugenio Fardella, Yunlin Zhang, Raymone Pajarillo, Linhui Chen, Ositadimma Ugwuanyi, Kelly Markowitz, Devora Delman, Mathew G. Angelos, Olga Shestova, Yusuke Isshiki, Marco Ruella
{"title":"EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models","authors":"Patrizia Porazzi, Siena Nason, Ziqi Yang, Alberto Carturan, Guido Ghilardi, Puneeth Guruprasad, Ruchi P. Patel, Melody Tan, Anushka Anant Padmanabhan, Jean Lemoine, Eugenio Fardella, Yunlin Zhang, Raymone Pajarillo, Linhui Chen, Ositadimma Ugwuanyi, Kelly Markowitz, Devora Delman, Mathew G. Angelos, Olga Shestova, Yusuke Isshiki, Marco Ruella","doi":"10.1016/j.ccell.2025.01.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.013","url":null,"abstract":"Tumor resistance to chimeric antigen receptor T cell (CAR-T) and, in general, to adoptive cell immunotherapies (ACTs) is a major challenge in the clinic. We hypothesized that inhibiting the tumor drivers’ methyltransferases EZH2 and EZH1 could enhance ACT by rewiring cancer cells to a more immunogenic state. In human B cell lymphoma, EZH2 inhibition (tazemetostat) improved the efficacy of anti-CD19 CAR-T by enhancing activation, expansion, and tumor infiltration. Mechanistically, tazemetostat-treated tumors showed upregulation of genes related to adhesion, B cell activation, and inflammatory responses, and increased avidity to CAR-T. Furthermore, tazemetostat improved CAR- and TCR-engineered T cell efficacy in multiple liquid (myeloma and acute myeloid leukemia) and solid (sarcoma, ovarian, and prostate) cancers. Lastly, combined EZH1/EZH2 inhibition (valemetostat) further boosted CAR-T efficacy and expansion in multiple cancers. This study shows that EZH1/2 inhibition reprograms tumors to a more immunogenic state and potentiates ACT in preclinical models of both liquid and solid cancers.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"17 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451884","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 : 2025-02-20DOI: 10.1016/j.ccell.2025.01.012
Haiquan Chen, Chaoqiang Deng, Jian Gao, Jun Wang, Fangqiu Fu, Yue Wang, Qiming Wang, Mou Zhang, Shiyue Zhang, Fanfan Fan, Kun Liu, Bo Yang, Qiming He, Qiang Zheng, Xuxia Shen, Jin Wang, Tao Hu, Changbin Zhu, Fei Yang, Yonghong He, Zhiwei Cao
{"title":"Integrative spatial analysis reveals tumor heterogeneity and immune colony niche related to clinical outcomes in small cell lung cancer","authors":"Haiquan Chen, Chaoqiang Deng, Jian Gao, Jun Wang, Fangqiu Fu, Yue Wang, Qiming Wang, Mou Zhang, Shiyue Zhang, Fanfan Fan, Kun Liu, Bo Yang, Qiming He, Qiang Zheng, Xuxia Shen, Jin Wang, Tao Hu, Changbin Zhu, Fei Yang, Yonghong He, Zhiwei Cao","doi":"10.1016/j.ccell.2025.01.012","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.012","url":null,"abstract":"Recent advances have shed light on the molecular heterogeneity of small cell lung cancer (SCLC), yet the spatial organizations and cellular interactions in tumor immune microenvironment remain to be elucidated. Here, we employ co-detection by indexing (CODEX) and multi-omics profiling to delineate the spatial landscape for 165 SCLC patients, generating 267 high-dimensional images encompassing over 9.3 million cells. Integrating CODEX and genomic data reveals a multi-positive tumor cell neighborhood within ASCL1<sup>+</sup> (SCLC-A) subtype, characterized by high SLFN11 expression and associated with poor prognosis. We further develop a cell colony detection algorithm (ColonyMap) and reveal a spatially assembled immune niche consisting of antitumoral macrophages, CD8<sup>+</sup> T cells and natural killer T cells (MT<sup>2</sup>) which highly correlates with superior survival and predicts improving immunotherapy response in an independent cohort. This study serves as a valuable resource to study SCLC spatial heterogeneity and offers insights into potential patient stratification and personalized treatments.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"11 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451888","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 : 2025-02-10DOI: 10.1016/j.ccell.2025.01.005
Lorenzo Galluzzi, Emma Guilbaud, Abhishek D. Garg
{"title":"Mitochondrial succinate feeds T cell exhaustion in cancer","authors":"Lorenzo Galluzzi, Emma Guilbaud, Abhishek D. Garg","doi":"10.1016/j.ccell.2025.01.005","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.005","url":null,"abstract":"Mitochondrial fitness is critical for effector CD8<sup>+</sup> T cell responses against cancer. In this issue of <em>Cancer Cell</em>, Ma et al. delineate a novel mechanism linking defects in mitochondrial metabolism as elicited by prolyl 4-hydroxylase subunit alpha 1 (P4HA1) to T cell exhaustion and reduced tumor sensitivity to immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"12 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375419","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":"Immunosensitivity cuts across mismatch repair status in colorectal cancer","authors":"Allyson Moraig Peddle, Gertjan Rasschaert, Sabine Tejpar","doi":"10.1016/j.ccell.2025.01.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.010","url":null,"abstract":"In this issue of <em>Cancer Cell</em>, Acha-Sagredo et al. reveal an interferon-high immunophenotype in colorectal cancer that predicts responsiveness to immune checkpoint inhibitors across both mismatch repair-deficient and mismatch repair-proficient subtypes. They identify CD74 as a biomarker and establish the importance of epithelial interferon levels in regulating immune responses.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"144 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375421","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 : 2025-02-10DOI: 10.1016/j.ccell.2025.01.009
Julia Schiantarelli, Mouadh Benamar, Jihye Park, Haley E. Sax, Giacomo Oliveira, Alice Bosma-Moody, Katie M. Campbell, David Liu, Douglas B. Johnson, Scott Rodig, Catherine J. Wu, F. Stephen Hodi, Antoni Ribas, Eliezer Van Allen, Rizwan Haq
{"title":"Genomic mediators of acquired resistance to immunotherapy in metastatic melanoma","authors":"Julia Schiantarelli, Mouadh Benamar, Jihye Park, Haley E. Sax, Giacomo Oliveira, Alice Bosma-Moody, Katie M. Campbell, David Liu, Douglas B. Johnson, Scott Rodig, Catherine J. Wu, F. Stephen Hodi, Antoni Ribas, Eliezer Van Allen, Rizwan Haq","doi":"10.1016/j.ccell.2025.01.009","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.009","url":null,"abstract":"Although some patients with metastatic melanoma experience durable responses to immune checkpoint inhibitors (ICIs), most exhibit intrinsic or acquired resistance to these therapies. Here, we compare somatic genomic profiles from matched pre-treatment and post-resistance tumor biopsies in patients (<em>n</em> = 25) with metastatic melanoma who exhibited heterogeneous ICI responses to nominate additional mediators of acquired resistance. We find that several acquired resistance tumors exhibit defects in <em>B2M</em> or <em>JAK1/2</em>, consistent with prior findings. We also discover resistance-associated mutations in <em>SEC24C</em> and <em>SEC24D</em> in 3 patients. SEC24 has an essential role in the trafficking of the dsDNA sensor STING and has been linked to interferonopathies. Melanoma cells engineered to express the <em>SEC24C</em> mutations observed in patients exhibit diminished STING signaling, including decreased type I interferon production, antigen presentation, and a reduced capacity to activate cytotoxic T cells. This study nominates a role for aberrant STING trafficking in acquired resistance to ICIs.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"26 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375425","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 : 2025-02-10DOI: 10.1016/j.ccell.2025.01.004
Lukas M. Braun, Sophie Giesler, Geoffroy Andrieux, Roxane Riemer, Nana Talvard-Balland, Sandra Duquesne, Tamina Rückert, Susanne Unger, Stefanie Kreutmair, Melissa Zwick, Marie Follo, Alina Hartmann, Natascha Osswald, Wolfgang Melchinger, Stefanie Chapman, James A. Hutchinson, Sebastian Haferkamp, Leopold Torster, Julian Kött, Christoffer Gebhardt, Robert Zeiser
{"title":"Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity","authors":"Lukas M. Braun, Sophie Giesler, Geoffroy Andrieux, Roxane Riemer, Nana Talvard-Balland, Sandra Duquesne, Tamina Rückert, Susanne Unger, Stefanie Kreutmair, Melissa Zwick, Marie Follo, Alina Hartmann, Natascha Osswald, Wolfgang Melchinger, Stefanie Chapman, James A. Hutchinson, Sebastian Haferkamp, Leopold Torster, Julian Kött, Christoffer Gebhardt, Robert Zeiser","doi":"10.1016/j.ccell.2025.01.004","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.01.004","url":null,"abstract":"Immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that anti-tumor immunity is preserved in mice after extracorporeal photopheresis (ECP) but reduced with glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition. Local adiponectin production elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies in the colon while sparing tumor-specific T cell development. A prospective phase-1b/2 trial (EudraCT-No.2021-002073-26) with 14 patients reveals low ECP-related toxicity. Overall response rate for all irAEs is 92% (95% confidence interval [CI]: 63.97%–99.81%); colitis-specific complete remission rate is 100% (95% CI: 63.06%–100%). Glucocorticosteroid dosages could be reduced for all patients after ECP therapy. The ECP-adiponectin axis reduces intestinal tissue-resident memory T cell activation and CD4<sup>+</sup>IFN-γ<sup>+</sup> T cells in patients with ICI-induced colitis without evidence of loss of anti-tumor immunity. In conclusion, we identify adiponectin as an immunomodulatory molecule that controls ICI-induced irAEs without blocking anti-tumor immunity.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"50 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375424","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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