Pub Date : 2025-11-10Epub Date: 2025-10-23DOI: 10.1016/j.ccell.2025.09.013
Alexander Biederstädt, Katayoun Rezvani
Allogeneic natural killer (NK) cell immunotherapy is emerging as a promising and scalable, off-the-shelf platform for treating relapsed and refractory cancers. Early-phase clinical trials have demonstrated remarkable safety and encouraging therapeutic efficacy of chimeric antigen receptor (CAR)-NK cells in heavily pretreated patients with lymphoid malignancies. Current efforts are expanding these therapies to solid tumors, with translational research increasingly leveraging precision gene editing to enhance effector function, persistence, and resistance to the immunosuppressive tumor microenvironment. In this review, we summarize findings from early-phase clinical trials and discuss emerging synthetic biology and engineering approaches to improve NK cell potency. We also highlight advances in high-throughput discovery platforms that have identified actionable gene targets for NK cell reprogramming, offering a path to design multi-engineered CAR-NK cells to overcome the challenges of solid tumors. Together, these translational innovations define the trajectory of next-generation NK cell therapies and their integration into the broader cancer immunotherapy landscape.
{"title":"Engineered natural killer cells for cancer therapy.","authors":"Alexander Biederstädt, Katayoun Rezvani","doi":"10.1016/j.ccell.2025.09.013","DOIUrl":"10.1016/j.ccell.2025.09.013","url":null,"abstract":"<p><p>Allogeneic natural killer (NK) cell immunotherapy is emerging as a promising and scalable, off-the-shelf platform for treating relapsed and refractory cancers. Early-phase clinical trials have demonstrated remarkable safety and encouraging therapeutic efficacy of chimeric antigen receptor (CAR)-NK cells in heavily pretreated patients with lymphoid malignancies. Current efforts are expanding these therapies to solid tumors, with translational research increasingly leveraging precision gene editing to enhance effector function, persistence, and resistance to the immunosuppressive tumor microenvironment. In this review, we summarize findings from early-phase clinical trials and discuss emerging synthetic biology and engineering approaches to improve NK cell potency. We also highlight advances in high-throughput discovery platforms that have identified actionable gene targets for NK cell reprogramming, offering a path to design multi-engineered CAR-NK cells to overcome the challenges of solid tumors. Together, these translational innovations define the trajectory of next-generation NK cell therapies and their integration into the broader cancer immunotherapy landscape.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1987-2013"},"PeriodicalIF":44.5,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12631954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367656","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}
Pub Date : 2025-11-10Epub Date: 2025-10-24DOI: 10.1016/j.ccell.2025.10.005
Wenjing Su, Hyun Ho Han, Yan Wang, Boyu Zhang, Bing Zhou, Yuanming Cheng, Alekya Rumandla, Sreeharsha Gurrapu, Goutam Chakraborty, Jie Su, Guangli Yang, Xin Liang, Guocan Wang, Neal Rosen, Howard I Scher, Ouathek Ouerfelli, Filippo G Giancotti
{"title":"The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression.","authors":"Wenjing Su, Hyun Ho Han, Yan Wang, Boyu Zhang, Bing Zhou, Yuanming Cheng, Alekya Rumandla, Sreeharsha Gurrapu, Goutam Chakraborty, Jie Su, Guangli Yang, Xin Liang, Guocan Wang, Neal Rosen, Howard I Scher, Ouathek Ouerfelli, Filippo G Giancotti","doi":"10.1016/j.ccell.2025.10.005","DOIUrl":"10.1016/j.ccell.2025.10.005","url":null,"abstract":"","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"2171-2173"},"PeriodicalIF":44.5,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370206","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}
Total neoadjuvant therapy (TNT) is a standard care for locally advanced rectal cancer (LARC), yet the immune remodeling mechanisms underlying its efficacy remain unclear. Using single-cell RNA, T cell receptor, and spatial transcriptome sequencing of matched pre- and post-treatment samples, we depicted the tumor microenvironment (TME) dynamics induced by different neoadjuvant therapies. TNT is associated with reduced regulatory T cells and increased IFNG+CD8+ effector memory T cells with high IFNG expression, potentially contributing to improved complete response rates. The abundance of tumor-infiltrating CD8+ T cells is correlated with the enrichment of the ACKR1+ endothelial subset after TNT. We further validated that endothelial cells (ECs), when stimulated by IFNγ, potentially released by CD8+ T cells, acquire an enhanced ability for presenting antigens and activating CD8+ T cells. Together, our study systematically characterizes the TME dynamics and uncovers the unique interaction between activated CD8+ T cells and ECs after TNT.
{"title":"Remodeling of T and endothelial cells during total neoadjuvant therapy in rectal cancer","authors":"Qianqian Gao, Xinnan Ling, Leen Liao, Fei Tang, Yujia Jiang, Shishang Qin, Wenhong Hou, Wei Zhou, Lijuan Jiang, Chunman Xiao, Yufei Bo, Yuhui Miao, Hai-xi Sun, Ruoyao Wang, Kezhuo Yu, Qiaoqi Sui, Shijie Hao, Weijian Mei, Dongfang Wang, Xiuqing Zhang, Sijin Cheng, Linnan Zhu, Peirong Ding, Zemin Zhang","doi":"10.1016/j.ccell.2025.10.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.10.008","url":null,"abstract":"Total neoadjuvant therapy (TNT) is a standard care for locally advanced rectal cancer (LARC), yet the immune remodeling mechanisms underlying its efficacy remain unclear. Using single-cell RNA, T cell receptor, and spatial transcriptome sequencing of matched pre- and post-treatment samples, we depicted the tumor microenvironment (TME) dynamics induced by different neoadjuvant therapies. TNT is associated with reduced regulatory T cells and increased IFNG<sup>+</sup>CD8<sup>+</sup> effector memory T cells with high IFNG expression, potentially contributing to improved complete response rates. The abundance of tumor-infiltrating CD8<sup>+</sup> T cells is correlated with the enrichment of the ACKR1<sup>+</sup> endothelial subset after TNT. We further validated that endothelial cells (ECs), when stimulated by IFNγ, potentially released by CD8<sup>+</sup> T cells, acquire an enhanced ability for presenting antigens and activating CD8<sup>+</sup> T cells. Together, our study systematically characterizes the TME dynamics and uncovers the unique interaction between activated CD8<sup>+</sup> T cells and ECs after TNT.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"1 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447681","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 : 2025-11-06DOI: 10.1016/j.ccell.2025.10.006
Xen Ping Hoi, Mary M. Stangis, Sarah E. Glass, Jin-Hee Kim, Seung Woo Kang, W. Nathaniel Brennen, Ziyi Li, William M. Grady, Srinivasan Yegnasubramanian, Peter Kuhn, Costas A. Lyssiotis, Akiko Sagara, Martha J. Shrubsole, Humam Kadara, Ying Yuan, Robert J. Coffey, Ken S. Lau, Angelo M. De Marzo, Anirban Maitra, Jimin Min, Ming Yu, Keith S. Chan
Cellular senescence plays dual roles in precancer lesions: initially serving as a tumor-suppressive barrier within the epithelial compartment and later contributing to a pro-tumoral precancer tissue microenvironment (PreTME) via a sustained, paracrine secretome known as senescent-associated secretory phenotype (SASP). This commentary highlights the role of senescence across various PreTME cell types, explores emerging pharmacologic and lifestyle interception strategies, and outlines current challenges for advancing biomarkers and clinical translation.
{"title":"Cellular senescence in precancer lesions and early-stage cancers","authors":"Xen Ping Hoi, Mary M. Stangis, Sarah E. Glass, Jin-Hee Kim, Seung Woo Kang, W. Nathaniel Brennen, Ziyi Li, William M. Grady, Srinivasan Yegnasubramanian, Peter Kuhn, Costas A. Lyssiotis, Akiko Sagara, Martha J. Shrubsole, Humam Kadara, Ying Yuan, Robert J. Coffey, Ken S. Lau, Angelo M. De Marzo, Anirban Maitra, Jimin Min, Ming Yu, Keith S. Chan","doi":"10.1016/j.ccell.2025.10.006","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.10.006","url":null,"abstract":"Cellular senescence plays dual roles in precancer lesions: initially serving as a tumor-suppressive barrier within the epithelial compartment and later contributing to a pro-tumoral precancer tissue microenvironment (PreTME) via a sustained, paracrine secretome known as senescent-associated secretory phenotype (SASP). This commentary highlights the role of senescence across various PreTME cell types, explores emerging pharmacologic and lifestyle interception strategies, and outlines current challenges for advancing biomarkers and clinical translation.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"56 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447214","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 : 2025-11-06DOI: 10.1016/j.ccell.2025.10.004
Fuduan Peng, Ansam Sinjab, Yibo Dai, Warapen Treekitkarnmongkol, Sujuan Yang, Lorena I. Gomez Bolanos, Tieling Zhou, Minyue Chen, Alejandra G. Serrano, Avantika Krishna, Nastaran Karimi, Manvi Sharma, Akshay Basi, Guangsheng Pei, Jianlong Liao, Yunhe Liu, Jiping Feng, Zahraa Rahal, Yang Liu, Jiahui Jiang, Kai Yu, Tala Noun, Yuejiang Liu, Khaja Khan, Kyung Serk Cho, Jichao Chen, Luisa M. Solis, Sarah Mazzilli, Steven Dubinett, Tina Cascone, Avrum E. Spira, Stephen Swisher, Naoe Jimbo, Takuo Hayashi, Satsuki Kishikawa, Kazuya Takamochi, Tomoo Itoh, Takashi Yao, Kenji Suzuki, Neda Kalhor, Ignacio I. Wistuba, Mingyao Li, Seyed Javad Moghaddam, Junya Fujimoto, Jared Burks, Jeffrey Myers, Kadir Akdemir, Linghua Wang, Humam Kadara
The co-evolution of different cell subsets in the progression of precursor lesions to lung adenocarcinoma (LUAD) is incompletely understood. We generated spatial transcriptomic maps of 56 human precursor lesions and LUADs from 25 patients and of an independent cohort of 36 lesions from 19 patients, analyzing a total of 486,519 spots and 5.4 million cells. We identify region-specific programs that distinguish precursors from LUADs. Spatially resolved clonal architectures reveal patient-specific heterogeneity in evolution of precursors to LUADs. We find epithelial alveolar progenitors expressing tumor-associated meta-programs and residing in niches enriched with proinflammatory subsets including IL1B high macrophages. Epithelial-proinflammatory niches are prevalent in precursor lesions but become less frequent in LUADs. These niches are conserved in mice and promote alveolar progenitor growth. Targeting inflammation alone or in combination with immune checkpoint blockade in precancerous phase reduces alveolar progenitors. Epithelial-inflammatory niches are stage-specific, shape early LUAD development and represent promising targets for interception.
{"title":"Multimodal spatial-omics reveal co-evolution of alveolar progenitors and proinflammatory niches in progression of lung precursor lesions","authors":"Fuduan Peng, Ansam Sinjab, Yibo Dai, Warapen Treekitkarnmongkol, Sujuan Yang, Lorena I. Gomez Bolanos, Tieling Zhou, Minyue Chen, Alejandra G. Serrano, Avantika Krishna, Nastaran Karimi, Manvi Sharma, Akshay Basi, Guangsheng Pei, Jianlong Liao, Yunhe Liu, Jiping Feng, Zahraa Rahal, Yang Liu, Jiahui Jiang, Kai Yu, Tala Noun, Yuejiang Liu, Khaja Khan, Kyung Serk Cho, Jichao Chen, Luisa M. Solis, Sarah Mazzilli, Steven Dubinett, Tina Cascone, Avrum E. Spira, Stephen Swisher, Naoe Jimbo, Takuo Hayashi, Satsuki Kishikawa, Kazuya Takamochi, Tomoo Itoh, Takashi Yao, Kenji Suzuki, Neda Kalhor, Ignacio I. Wistuba, Mingyao Li, Seyed Javad Moghaddam, Junya Fujimoto, Jared Burks, Jeffrey Myers, Kadir Akdemir, Linghua Wang, Humam Kadara","doi":"10.1016/j.ccell.2025.10.004","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.10.004","url":null,"abstract":"The co-evolution of different cell subsets in the progression of precursor lesions to lung adenocarcinoma (LUAD) is incompletely understood. We generated spatial transcriptomic maps of 56 human precursor lesions and LUADs from 25 patients and of an independent cohort of 36 lesions from 19 patients, analyzing a total of 486,519 spots and 5.4 million cells. We identify region-specific programs that distinguish precursors from LUADs. Spatially resolved clonal architectures reveal patient-specific heterogeneity in evolution of precursors to LUADs. We find epithelial alveolar progenitors expressing tumor-associated meta-programs and residing in niches enriched with proinflammatory subsets including <em>IL1B</em> high macrophages. Epithelial-proinflammatory niches are prevalent in precursor lesions but become less frequent in LUADs. These niches are conserved in mice and promote alveolar progenitor growth. Targeting inflammation alone or in combination with immune checkpoint blockade in precancerous phase reduces alveolar progenitors. Epithelial-inflammatory niches are stage-specific, shape early LUAD development and represent promising targets for interception.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"32 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447218","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}
The spatial landscape of the tumor immune microenvironment (TIME) is under significant investigation as a driver of immunotherapy resistance in solid tumors. Most work centers on constituent immune cells within intra-tumoral niches, overlooking tumor cell phenotypes. Yet cancer cells shape their milieu by multiple modalities, including secreting and depleting metabolites. Here, we argue that integrating cancer cell phenotypic heterogeneity into spatial analyses is essential to reveal the mechanisms that generate TIME diversity and to better address resistance to immunotherapy.
{"title":"Decoding the spatial dynamics of tumor and immune cell interactions in solid cancers","authors":"Eleanor Minogue, Pilar Baldominos, Lauren Hsu, Marcia C. Haigis, Judith Agudo","doi":"10.1016/j.ccell.2025.10.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.10.007","url":null,"abstract":"The spatial landscape of the tumor immune microenvironment (TIME) is under significant investigation as a driver of immunotherapy resistance in solid tumors. Most work centers on constituent immune cells within intra-tumoral niches, overlooking tumor cell phenotypes. Yet cancer cells shape their milieu by multiple modalities, including secreting and depleting metabolites. Here, we argue that integrating cancer cell phenotypic heterogeneity into spatial analyses is essential to reveal the mechanisms that generate TIME diversity and to better address resistance to immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"2 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447677","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 : 2025-11-06DOI: 10.1016/j.ccell.2025.10.003
Artur Rebelo, Thomas Seufferlein, Jorg Kleeff
For resectable pancreatic cancer, upfront surgery followed by adjuvant therapy has long been the standard of care. A randomized trial by Bai et al. in Cancer Cell demonstrates that sequential neoadjuvant gemcitabine/nab-paclitaxel followed by mFOLFIRINOX significantly improved event-free survival compared with upfront surgery, supporting a shift toward a sequential neoadjuvant approach in this setting.
{"title":"Toward a new standard: Sequential multi-agent neoadjuvant chemotherapy in resectable pancreatic cancer","authors":"Artur Rebelo, Thomas Seufferlein, Jorg Kleeff","doi":"10.1016/j.ccell.2025.10.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.10.003","url":null,"abstract":"For resectable pancreatic cancer, upfront surgery followed by adjuvant therapy has long been the standard of care. A randomized trial by Bai et al. in <em>Cancer Cell</em> demonstrates that sequential neoadjuvant gemcitabine/nab-paclitaxel followed by mFOLFIRINOX significantly improved event-free survival compared with upfront surgery, supporting a shift toward a sequential neoadjuvant approach in this setting.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"39 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447680","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 : 2025-10-30DOI: 10.1016/j.ccell.2025.10.002
Bassel Ghaddar, Subhajyoti De, Martin J. Blaser
{"title":"Fusobacterium, quiescent niches, and therapy response in colorectal cancer","authors":"Bassel Ghaddar, Subhajyoti De, Martin J. Blaser","doi":"10.1016/j.ccell.2025.10.002","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.10.002","url":null,"abstract":"","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"27 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145396754","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 : 2025-10-23DOI: 10.1016/j.ccell.2025.09.014
Eli L Diamond, Jean-Francois Emile, Takeshi Fujino, Julien Haroche, Maxim I Maron, Alexander M Lewis, Jahan Rahman, Anne S Reiner, Dana Bossert, Marc Rosenblum, Mariko Yabe, Kseniya Petrova-Drus, Jasmine H Francis, Veronica Rotemberg, Raajit K Rampal, Sarah Yoo, Anthony F Daniyan, Sonia Mahajan, Vaios Hatzoglou, Robert Young, Gary A Ulaner, Wiebke Rösler, Oshrat Hershkovitz-Rokah, Ofer Shpilberg, Roei D Mazor, Luke Y C Chen, Michael Singer, M Adriana Cuibus, Kenyon Weis, Salima Benbarche, Pu Zhang, Nina Fox, Cynthia Castro, Steven Tittley, Matthew Witkowski, Fleur Cohen-Aubart, Louis Terriou, Maher Hanoun, Nicolas Schleinitz, Gabriela Sosa, Timo Hautala, Laure Farnault De Lassus, Neal Rosen, Omar Abdel-Wahab, Benjamin H Durham
Histiocytic neoplasms are clonal disorders of the monocyte/macrophage lineage defined by mutations activating mitogen-activated protein kinase (MAPK) signaling. Recently, the MEK1/2 inhibitor cobimetinib was FDA-approved for patients with adult histiocytoses. Here, aided by a prospective registry of patients with histiocytoses (NCT03329274), we identify that MEK1/2 mutations which constitutively activate MEK independently of RAF are associated with worse progression-free survival with MEK1/2 inhibition as compared to patients with other MEK1/2 mutational classes. The most common RAF-independent MEK1 mutation (MEK1E102_I103del) drove a lethal histiocytic-like neoplasm in mice, which was sensitive to the ERK1/2 inhibitor ulixertinib. We subsequently treated five MEK1E102_I103del-mutant patients with ulixertinib on prospective protocols, four of whom were refractory to MEK inhibition. Four of five patients experienced objective responses to ulixertinib. These data reveal the impact of oncogenic MEK mutations in vivo, identify patients with likelihood of resistance to MEK inhibition, and nominate ERK inhibition to overcome resistance to MEK inhibition in histiocytoses.
{"title":"RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition.","authors":"Eli L Diamond, Jean-Francois Emile, Takeshi Fujino, Julien Haroche, Maxim I Maron, Alexander M Lewis, Jahan Rahman, Anne S Reiner, Dana Bossert, Marc Rosenblum, Mariko Yabe, Kseniya Petrova-Drus, Jasmine H Francis, Veronica Rotemberg, Raajit K Rampal, Sarah Yoo, Anthony F Daniyan, Sonia Mahajan, Vaios Hatzoglou, Robert Young, Gary A Ulaner, Wiebke Rösler, Oshrat Hershkovitz-Rokah, Ofer Shpilberg, Roei D Mazor, Luke Y C Chen, Michael Singer, M Adriana Cuibus, Kenyon Weis, Salima Benbarche, Pu Zhang, Nina Fox, Cynthia Castro, Steven Tittley, Matthew Witkowski, Fleur Cohen-Aubart, Louis Terriou, Maher Hanoun, Nicolas Schleinitz, Gabriela Sosa, Timo Hautala, Laure Farnault De Lassus, Neal Rosen, Omar Abdel-Wahab, Benjamin H Durham","doi":"10.1016/j.ccell.2025.09.014","DOIUrl":"10.1016/j.ccell.2025.09.014","url":null,"abstract":"<p><p>Histiocytic neoplasms are clonal disorders of the monocyte/macrophage lineage defined by mutations activating mitogen-activated protein kinase (MAPK) signaling. Recently, the MEK1/2 inhibitor cobimetinib was FDA-approved for patients with adult histiocytoses. Here, aided by a prospective registry of patients with histiocytoses (NCT03329274), we identify that MEK1/2 mutations which constitutively activate MEK independently of RAF are associated with worse progression-free survival with MEK1/2 inhibition as compared to patients with other MEK1/2 mutational classes. The most common RAF-independent MEK1 mutation (MEK1<sup>E102_I103del</sup>) drove a lethal histiocytic-like neoplasm in mice, which was sensitive to the ERK1/2 inhibitor ulixertinib. We subsequently treated five MEK1<sup>E102_I103del</sup>-mutant patients with ulixertinib on prospective protocols, four of whom were refractory to MEK inhibition. Four of five patients experienced objective responses to ulixertinib. These data reveal the impact of oncogenic MEK mutations in vivo, identify patients with likelihood of resistance to MEK inhibition, and nominate ERK inhibition to overcome resistance to MEK inhibition in histiocytoses.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":""},"PeriodicalIF":44.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12616613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367623","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}
Pub Date : 2025-10-16DOI: 10.1016/j.ccell.2025.09.010
Jorge Luis Galeano Niño, Falk Ponath, Victor A. Ajisafe, Clara R. Becker, Andrew G. Kempchinsky, Martha A. Zepeda-Rivera, Javier A. Gomez, Hanrui Wu, Jessica G. Terrazas, Heather Bouzek, Elizabeth Cromwell, Pritha Chanana, Matthew Wong, Ashish Damania, Michael G. White, Y. Nancy You, Scott Kopetz, Nadim J. Ajami, Jennifer A. Wargo, Christopher D. Johnston, Susan Bullman
Tumor-infiltrating bacteria are increasingly recognized as modulators of cancer progression and therapy resistance. We describe a mechanism by which extracellular intratumoral bacteria, including Fusobacterium, modulate cancer epithelial cell behavior. Spatial imaging and single-cell spatial transcriptomics show that these bacteria predominantly localize extracellularly within tumor microniches of colorectal and oral cancers, characterized by reduced cell density, transcriptional activity, and proliferation. In vitro, Fusobacterium nucleatum disrupts epithelial contacts, inducing G0-G1 arrest and transcriptional quiescence. This state confers 5-fluorouracil resistance and remodels the tumor microenvironment. Findings were validated by live-cell imaging, spatial profiling, mouse models, and a 52-patient colorectal cancer cohort. Transcriptomics reveals downregulation of cell cycle, transcription, and antigen presentation genes in bacteria-enriched regions, consistent with a quiescent, immune-evasive phenotype. In an independent rectal cancer cohort, high Fusobacterium burden correlates with reduced therapy response. These results link extracellular bacteria to cancer cell quiescence and chemoresistance, highlighting microbial-tumor interactions as therapeutic targets.
{"title":"Tumor-infiltrating bacteria disrupt cancer epithelial cell interactions and induce cell-cycle arrest","authors":"Jorge Luis Galeano Niño, Falk Ponath, Victor A. Ajisafe, Clara R. Becker, Andrew G. Kempchinsky, Martha A. Zepeda-Rivera, Javier A. Gomez, Hanrui Wu, Jessica G. Terrazas, Heather Bouzek, Elizabeth Cromwell, Pritha Chanana, Matthew Wong, Ashish Damania, Michael G. White, Y. Nancy You, Scott Kopetz, Nadim J. Ajami, Jennifer A. Wargo, Christopher D. Johnston, Susan Bullman","doi":"10.1016/j.ccell.2025.09.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.09.010","url":null,"abstract":"Tumor-infiltrating bacteria are increasingly recognized as modulators of cancer progression and therapy resistance. We describe a mechanism by which extracellular intratumoral bacteria, including <em>Fusobacterium</em>, modulate cancer epithelial cell behavior. Spatial imaging and single-cell spatial transcriptomics show that these bacteria predominantly localize extracellularly within tumor microniches of colorectal and oral cancers, characterized by reduced cell density, transcriptional activity, and proliferation. <em>In vitro</em>, <em>Fusobacterium nucleatum</em> disrupts epithelial contacts, inducing G0-G1 arrest and transcriptional quiescence. This state confers 5-fluorouracil resistance and remodels the tumor microenvironment. Findings were validated by live-cell imaging, spatial profiling, mouse models, and a 52-patient colorectal cancer cohort. Transcriptomics reveals downregulation of cell cycle, transcription, and antigen presentation genes in bacteria-enriched regions, consistent with a quiescent, immune-evasive phenotype. In an independent rectal cancer cohort, high <em>Fusobacterium</em> burden correlates with reduced therapy response. These results link extracellular bacteria to cancer cell quiescence and chemoresistance, highlighting microbial-tumor interactions as therapeutic targets.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"58 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295526","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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