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 : 2025-10-16DOI: 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}
Pub Date : 2025-10-16DOI: 10.1016/j.ccell.2025.09.011
Shelley Herbrich, Mehdi Chaib, Swetha Anandhan, Samuel W. Andrewes, Ashwat Nagarajan, Baoxiang Guan, Nishant Gandhi, Jared Gilliam, Milan Radovich, Padmanee Sharma
Clonal hematopoiesis (CH) is detectable in upwards of 20% of patients with solid tumors and is associated with worsened prognosis; however, its role in tumor immunology and immune checkpoint therapy (ICT) is unknown. Using a bone marrow chimera model of Tet2+/mut CH in mice with solid tumors, we found the Tet2-mutant myeloid cells are abundant in the tumor microenvironment and contributed to an improved response to ICT. Mechanistically, Tet2+/mut macrophages inside the tumor act as immunogenic antigen-presenting cells that more effectively cross-prime naive CD8+ T cells in response to IFNγ. In human cohorts of 35,971 non-small cell lung cancer patients and 25,064 colorectal adenocarcinoma patients, TET2-mutant CH is associated with improved outcome specifically with ICT. This study proposes a role for Tet2+/mut antigen presenting macrophages in shaping antitumor immunity and identifies TET2-mutant CH as a potential biomarker for improved response to ICT in patients with solid tumors.
{"title":"TET2-mutant clonal hematopoiesis enhances macrophage antigen presentation and improves immune checkpoint therapy in solid tumors","authors":"Shelley Herbrich, Mehdi Chaib, Swetha Anandhan, Samuel W. Andrewes, Ashwat Nagarajan, Baoxiang Guan, Nishant Gandhi, Jared Gilliam, Milan Radovich, Padmanee Sharma","doi":"10.1016/j.ccell.2025.09.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.09.011","url":null,"abstract":"Clonal hematopoiesis (CH) is detectable in upwards of 20% of patients with solid tumors and is associated with worsened prognosis; however, its role in tumor immunology and immune checkpoint therapy (ICT) is unknown. Using a bone marrow chimera model of <em>Tet2</em><sup>+/mut</sup> CH in mice with solid tumors, we found the <em>Tet2</em>-mutant myeloid cells are abundant in the tumor microenvironment and contributed to an improved response to ICT. Mechanistically, <em>Tet2</em><sup>+/mut</sup> macrophages inside the tumor act as immunogenic antigen-presenting cells that more effectively cross-prime naive CD8<sup>+</sup> T cells in response to IFNγ. In human cohorts of 35,971 non-small cell lung cancer patients and 25,064 colorectal adenocarcinoma patients<em>, TET2-</em>mutant CH is associated with improved outcome specifically with ICT. This study proposes a role for <em>Tet2</em><sup>+/mut</sup> antigen presenting macrophages in shaping antitumor immunity and identifies <em>TET2-</em>mutant CH as a potential biomarker for improved response to ICT in patients with solid tumors.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"13 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295525","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 : 2025-10-09DOI: 10.1016/j.ccell.2025.09.008
Pashtoon Murtaza Kasi
Immunotherapy as single-agent PD-1 blockade does not work for patients with microsatellite stable (MSS) colorectal cancer. In this issue of Cancer Cell, Morris et al. demonstrate that targeting the mitogen-activated protein kinase (MAPK) pathway in combination with immunotherapy can reprogram BRAF-V600E mutant MSS colorectal cancers toward immune responsiveness.
{"title":"Hidden spark: From cold to hot in BRAF colorectal cancer","authors":"Pashtoon Murtaza Kasi","doi":"10.1016/j.ccell.2025.09.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.09.008","url":null,"abstract":"Immunotherapy as single-agent PD-1 blockade does not work for patients with microsatellite stable (MSS) colorectal cancer. In this issue of <em>Cancer Cell</em>, Morris et al. demonstrate that targeting the mitogen-activated protein kinase (MAPK) pathway in combination with immunotherapy can reprogram BRAF-V600E mutant MSS colorectal cancers toward immune responsiveness.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"85 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247550","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 : 2025-10-09DOI: 10.1016/j.ccell.2025.09.009
Xueli Bai, Xiang Li, Yiwen Chen, Guoliang Qiao, Qi Zhang, Tao Ma, Shunliang Gao, Min Zhang, Yan Shen, Jian Wu, Jun Yu, Risheng Que, Xiaochen Zhang, Ke Sun, Wenbo Xiao, Tian’an Jiang, Tingbo Liang
This single-center, randomized phase 3 trial (NCT03750669) evaluated sequential neoadjuvant nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX versus upfront surgery in 324 patients with resectable pancreatic cancer. Patients in the neoadjuvant group received nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX before surgery and then four cycles of adjuvant therapy (preferably gemcitabine plus capecitabine), while those in the upfront surgery group underwent immediate resection followed by six cycles of adjuvant therapy. The primary endpoint was event-free survival. Notably, 50% of patients had tumors in the pancreatic body or tail. Median event-free survival was 15.3 months (95% confidence interval [CI], 12.6–19.3) versus 10.9 months (95% CI, 9.1–13.5; hazard ratio [HR], 0.71; 95% CI, 0.54–0.93; p = 0.0136). Median overall survival was 35.4 months versus 27.2 months (HR, 0.73; 95% CI, 0.53–1.00; nominal p = 0.0477). Grade ≥3 adverse events occurred in 47.6% versus 30.7% of patients. This neoadjuvant regimen improves event-free survival with manageable safety.
这项单中心、随机3期试验（NCT03750669）评估了324例可切除胰腺癌患者的序贯新辅助nab-紫杉醇加吉西他滨后改良FOLFIRINOX与前期手术的对比。新辅助组患者术前接受nab-紫杉醇+吉西他滨，随后改良FOLFIRINOX，然后进行4个周期的辅助治疗（最好是吉西他滨+卡培他滨），而术前组患者接受立即切除，然后进行6个周期的辅助治疗。主要终点为无事件生存期。值得注意的是，50%的患者在胰腺体或胰腺尾有肿瘤。中位无事件生存期为15.3个月（95%可信区间[CI]， 12.6-19.3） vs 10.9个月（95% CI, 9.1-13.5；风险比[HR]， 0.71; 95% CI, 0.54-0.93; p = 0.0136）。中位总生存期为35.4个月对27.2个月（HR, 0.73; 95% CI, 0.53-1.00；名义p = 0.0477）。≥3级不良事件发生率分别为47.6%和30.7%。这种新辅助方案提高了无事件生存和可控的安全性。
{"title":"Neoadjuvant nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX for resectable pancreatic cancer: A randomized phase 3 trial","authors":"Xueli Bai, Xiang Li, Yiwen Chen, Guoliang Qiao, Qi Zhang, Tao Ma, Shunliang Gao, Min Zhang, Yan Shen, Jian Wu, Jun Yu, Risheng Que, Xiaochen Zhang, Ke Sun, Wenbo Xiao, Tian’an Jiang, Tingbo Liang","doi":"10.1016/j.ccell.2025.09.009","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.09.009","url":null,"abstract":"This single-center, randomized phase 3 trial (NCT03750669) evaluated sequential neoadjuvant nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX versus upfront surgery in 324 patients with resectable pancreatic cancer. Patients in the neoadjuvant group received nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX before surgery and then four cycles of adjuvant therapy (preferably gemcitabine plus capecitabine), while those in the upfront surgery group underwent immediate resection followed by six cycles of adjuvant therapy. The primary endpoint was event-free survival. Notably, 50% of patients had tumors in the pancreatic body or tail. Median event-free survival was 15.3 months (95% confidence interval [CI], 12.6–19.3) versus 10.9 months (95% CI, 9.1–13.5; hazard ratio [HR], 0.71; 95% CI, 0.54–0.93; <em>p</em> = 0.0136). Median overall survival was 35.4 months versus 27.2 months (HR, 0.73; 95% CI, 0.53–1.00; nominal <em>p</em> = 0.0477). Grade ≥3 adverse events occurred in 47.6% versus 30.7% of patients. This neoadjuvant regimen improves event-free survival with manageable safety.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"68 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247551","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 : 2025-10-09DOI: 10.1016/j.ccell.2025.09.007
Francesco Di Meo, Francesca Albano, Annamaria Cesarano, Yunfei Wang, Brandon Kale, Kenneth Shain, Ariosto Silva, Noriyoshi Kurihara, Hirofumi Tenshin, David Jellyman, Xiaofei Song, Sasan Ghaffari, Hector Mesa, Ben Creelan, Ciara Freeman, Xiaohong Zhao, Mark B. Meads, Paulo C. Rodriguez, Silvia Marino, Frederick Locke, Fabiana Perna
Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) is effective, but relapses associated with low-to-negative BCMA expression are common, indicating the need for additional targets. We quantitatively profile antigen density in a cohort of patients relapsed after BCMA CAR T therapy, showing high number of SEMA4A molecules/cell where BCMA density is low. SEMA4A deletion limits MM cell growth, migration, tissue infiltration, and osteoclast formation, while extending mouse survival. We generate monoclonal antibodies targeting SEMA4A-extracellular domain for CAR construction, screen engineered T cells for expansion, cytokine release, and cytotoxicity against MM cells. Lead constructs lack reactivity against normal non-hematopoietic tissues. SEMA4A CAR T cells show superior efficacy than BCMA CAR T cells eliminating patient-derived BCMAlow tumors and MM cells progressing under suboptimal doses of BCMA CAR T cells. This study prepares for a phase 1 clinical trial with SEMA4A-directed CAR T cells for MM.
靶向B细胞成熟抗原（BCMA）的嵌合抗原受体（CAR） T细胞治疗多发性骨髓瘤（MM）是有效的，但与BCMA低至阴性表达相关的复发是常见的，这表明需要额外的靶点。我们定量分析了一组BCMA CAR - T治疗后复发患者的抗原密度，显示在BCMA密度低的地方，SEMA4A分子/细胞数量高。SEMA4A缺失限制了MM细胞的生长、迁移、组织浸润和破骨细胞的形成，同时延长了小鼠的存活时间。我们产生靶向sema4a细胞外结构域的单克隆抗体，用于CAR构建，筛选工程T细胞的扩增，细胞因子释放和对MM细胞的细胞毒性。铅构建体对正常非造血组织缺乏反应性。SEMA4A CAR - T细胞在次优剂量的BCMA CAR - T细胞下，对患者源性BCMAlow肿瘤和MM细胞的清除效果优于BCMA CAR - T细胞。该研究准备用sema4a靶向CAR - T细胞治疗MM的1期临床试验。
{"title":"Developing SEMA4A-directed CAR T cells to overcome low BCMA antigen density in multiple myeloma","authors":"Francesco Di Meo, Francesca Albano, Annamaria Cesarano, Yunfei Wang, Brandon Kale, Kenneth Shain, Ariosto Silva, Noriyoshi Kurihara, Hirofumi Tenshin, David Jellyman, Xiaofei Song, Sasan Ghaffari, Hector Mesa, Ben Creelan, Ciara Freeman, Xiaohong Zhao, Mark B. Meads, Paulo C. Rodriguez, Silvia Marino, Frederick Locke, Fabiana Perna","doi":"10.1016/j.ccell.2025.09.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.09.007","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) is effective, but relapses associated with low-to-negative BCMA expression are common, indicating the need for additional targets. We quantitatively profile antigen density in a cohort of patients relapsed after BCMA CAR T therapy, showing high number of SEMA4A molecules/cell where BCMA density is low. SEMA4A deletion limits MM cell growth, migration, tissue infiltration, and osteoclast formation, while extending mouse survival. We generate monoclonal antibodies targeting SEMA4A-extracellular domain for CAR construction, screen engineered T cells for expansion, cytokine release, and cytotoxicity against MM cells. Lead constructs lack reactivity against normal non-hematopoietic tissues. SEMA4A CAR T cells show superior efficacy than BCMA CAR T cells eliminating patient-derived BCMA<sup>low</sup> tumors and MM cells progressing under suboptimal doses of BCMA CAR T cells. This study prepares for a phase 1 clinical trial with SEMA4A-directed CAR T cells for MM.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"24 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247580","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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