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}
Pub Date : 2025-10-02DOI: 10.1016/j.ccell.2025.09.005
Julie F. Cheung, Brian G. Hunt, Shudipto Wahed, Elaine Cheng, Kelli A. Connolly, Srividhya Venkatesan, Jennifer L. Loza, Ishan Bansal, Eric Fagerberg, Emily A. Kessler, Clémence Riffard, Jessica Buck, John Attanasio, Emily R. Borr, Wei Wei, Ivana William, Brittany Fitzgerald, Nikhil S. Joshi
T cells edit tumors by eliminating neoantigen-expressing tumor cells. Yet, how and when this is achieved remains uncertain. Using a murine sarcoma model with fluorescent neoantigens, we found that tumors developed later and in fewer T cell-sufficient mice (∼53% penetrance) than T cell-deficient mice (∼100%). With T cells, all emergent tumor cells had silenced neoantigens, but neoantigen-negative tumor cells were also present in every T cell-deficient mouse. This suggested silencing was necessary but not sufficient for outgrowth. Genetic removal of neoantigens restored tumor penetrance if implemented on day 5 post-tumor initiation, but not day 10, because CD8+ and CD4+ T cells infiltrated the tissue and eliminated most neoantigen-positive and -negative tumor cells within 8 days. Single-cell analyses on day-7 tumors showed oncogenic changes including increased proliferation and T cell-dependent upregulation of the IFNγ-response gene Cd274 (PD-L1). T cell-depletion rescued both neoantigen-positive and -negative cells, while IFNγ blockade rescued only negative cells. This shows that T cells efficiently edit sarcomas of neoantigens and prevent early tumors via IFNγ-independent and IFNγ-dependent (bystander) mechanisms.
{"title":"Distinct T cell functions enable efficient immunoediting and prevent tumor emergence of developing sarcomas","authors":"Julie F. Cheung, Brian G. Hunt, Shudipto Wahed, Elaine Cheng, Kelli A. Connolly, Srividhya Venkatesan, Jennifer L. Loza, Ishan Bansal, Eric Fagerberg, Emily A. Kessler, Clémence Riffard, Jessica Buck, John Attanasio, Emily R. Borr, Wei Wei, Ivana William, Brittany Fitzgerald, Nikhil S. Joshi","doi":"10.1016/j.ccell.2025.09.005","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.09.005","url":null,"abstract":"T cells edit tumors by eliminating neoantigen-expressing tumor cells. Yet, how and when this is achieved remains uncertain. Using a murine sarcoma model with fluorescent neoantigens, we found that tumors developed later and in fewer T cell-sufficient mice (∼53% penetrance) than T cell-deficient mice (∼100%). With T cells, all emergent tumor cells had silenced neoantigens, but neoantigen-negative tumor cells were also present in every T cell-deficient mouse. This suggested silencing was necessary but not sufficient for outgrowth. Genetic removal of neoantigens restored tumor penetrance if implemented on day 5 post-tumor initiation, but not day 10, because CD8<sup>+</sup> and CD4<sup>+</sup> T cells infiltrated the tissue and eliminated most neoantigen-positive and -negative tumor cells within 8 days. Single-cell analyses on day-7 tumors showed oncogenic changes including increased proliferation and T cell-dependent upregulation of the IFNγ-response gene <em>Cd274</em> (PD-L1). T cell-depletion rescued both neoantigen-positive and -negative cells, while IFNγ blockade rescued only negative cells. This shows that T cells efficiently edit sarcomas of neoantigens and prevent early tumors via IFNγ-independent and IFNγ-dependent (bystander) mechanisms.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"2 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204007","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 : 2025-10-02DOI: 10.1016/j.ccell.2025.08.010
Giovanni Randon, Isacco Montroni, Filippo Pietrantonio
Upfront resection is the standard treatment for localized dMMR/MSI-high colon cancer. In this issue of Cancer Cell, Wang et al. showed that dual anti-CTLA-4/PD-1 IBI310/sintilimab for 6 weeks improved pathological complete response over sintilimab in patients with cT4/N+ tumors. This combination represents a referral regimen for neoadjuvant or organ-preserving strategies.
{"title":"Bringing immunotherapy to clinical practice in dMMR/MSI-high colon cancer","authors":"Giovanni Randon, Isacco Montroni, Filippo Pietrantonio","doi":"10.1016/j.ccell.2025.08.010","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.08.010","url":null,"abstract":"Upfront resection is the standard treatment for localized dMMR/MSI-high colon cancer. In this issue of <em>Cancer Cell</em>, Wang et al. showed that dual anti-CTLA-4/PD-1 IBI310/sintilimab for 6 weeks improved pathological complete response over sintilimab in patients with cT4/N+ tumors. This combination represents a referral regimen for neoadjuvant or organ-preserving strategies.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"113 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204004","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}
Although neoadjuvant immunotherapy showed promising efficacy in locally advanced microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) colon cancer, whether dual immune checkpoint inhibition provides additional benefit over anti-PD-1 monotherapy remains unclear. This randomized phase 1b trial (NCT05890742) evaluated a neoadjuvant regimen of IBI310 (anti-cytotoxic T lymphocyte-associated antigen 4 [CTLA-4]) plus sintilimab (n = 52) versus sintilimab monotherapy (n = 49). Surgery was performed in 51 and 45 patients, respectively. The primary endpoint, pathological complete response (pCR) rate, was significantly higher in the combination compared to the monotherapy arm within the modified intent-to-treat (mITT) population (78.4% versus 46.7%, p = 0.0015), with consistent results in the intent-to-treat (ITT) population (76.9% versus 42.9%). Safety in both arms was comparable and manageable without new safety signals. After a median follow-up of 21.4 months, no disease recurrences occurred. One death occurred in each arm due to postoperative complication and adverse events. These findings demonstrate the added benefit of neoadjuvant IBI310 plus sintilimab over sintilimab monotherapy for locally advanced MSI-H/dMMR colon cancer.
{"title":"Neoadjuvant treatment of IBI310 plus sintilimab in locally advanced MSI-H/dMMR colon cancer: A randomized phase 1b study","authors":"Feng Wang, Gong Chen, Meng Qiu, Jinfeng Ma, Xianwei Mo, Haiyi Liu, Yongqiang Li, Peirong Ding, Xiangbin Wan, Yingbin Hu, Xiwen Huang, Weiqin Jiang, Xiaojun Wu, Jia Luo, Yanbing Zhou, Leping Li, Yanlai Sun, Quan Wang, Nanya Wang, Wu Jiang, Rui-Hua Xu","doi":"10.1016/j.ccell.2025.09.004","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.09.004","url":null,"abstract":"Although neoadjuvant immunotherapy showed promising efficacy in locally advanced microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) colon cancer, whether dual immune checkpoint inhibition provides additional benefit over anti-PD-1 monotherapy remains unclear. This randomized phase 1b trial (<span><span>NCT05890742</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>) evaluated a neoadjuvant regimen of IBI310 (anti-cytotoxic T lymphocyte-associated antigen 4 [CTLA-4]) plus sintilimab (<em>n</em> = 52) versus sintilimab monotherapy (<em>n</em> = 49). Surgery was performed in 51 and 45 patients, respectively. The primary endpoint, pathological complete response (pCR) rate, was significantly higher in the combination compared to the monotherapy arm within the modified intent-to-treat (mITT) population (78.4% versus 46.7%, <em>p</em> = 0.0015), with consistent results in the intent-to-treat (ITT) population (76.9% versus 42.9%). Safety in both arms was comparable and manageable without new safety signals. After a median follow-up of 21.4 months, no disease recurrences occurred. One death occurred in each arm due to postoperative complication and adverse events. These findings demonstrate the added benefit of neoadjuvant IBI310 plus sintilimab over sintilimab monotherapy for locally advanced MSI-H/dMMR colon cancer.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"10 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204008","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 : 2025-10-02DOI: 10.1016/j.ccell.2025.09.006
W.H. Adrian Tsui, Peiyong Jiang, Y.M. Dennis Lo
The analysis of cell-free DNA (cfDNA) fragmentation patterns, known as “fragmentomics,” has opened new opportunities in noninvasive cancer diagnostics. Due to its close relationships with genomic organization and cell death, cfDNA fragmentomics lies at the intersection of many aspects of cancer biology, including epigenetic dysregulation, transcriptomic alterations, and aberrant cellular turnover patterns. Recent advances in library preparation, sequencing technologies, and integrative epigenomic-fragmentomic analyses have uncovered novel fragmentomic features that reveal specific cellular dysfunctions in cancer. Additionally, cutting-edge artificial intelligence algorithms now harness high-dimensional fragmentomic features, boosting the precision and power of cancer detection. Promising results from recent clinical trials evaluating the utility of fragmentomic analyses in real-world settings support its potential. In this review, we explore the exciting frontiers of cfDNA fragmentomics, discuss critical unanswered questions, and highlight future directions to unlock the promise of fragmentomics-based liquid biopsies in cancer care.
{"title":"Cell-free DNA fragmentomics in cancer","authors":"W.H. Adrian Tsui, Peiyong Jiang, Y.M. Dennis Lo","doi":"10.1016/j.ccell.2025.09.006","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.09.006","url":null,"abstract":"The analysis of cell-free DNA (cfDNA) fragmentation patterns, known as “fragmentomics,” has opened new opportunities in noninvasive cancer diagnostics. Due to its close relationships with genomic organization and cell death, cfDNA fragmentomics lies at the intersection of many aspects of cancer biology, including epigenetic dysregulation, transcriptomic alterations, and aberrant cellular turnover patterns. Recent advances in library preparation, sequencing technologies, and integrative epigenomic-fragmentomic analyses have uncovered novel fragmentomic features that reveal specific cellular dysfunctions in cancer. Additionally, cutting-edge artificial intelligence algorithms now harness high-dimensional fragmentomic features, boosting the precision and power of cancer detection. Promising results from recent clinical trials evaluating the utility of fragmentomic analyses in real-world settings support its potential. In this review, we explore the exciting frontiers of cfDNA fragmentomics, discuss critical unanswered questions, and highlight future directions to unlock the promise of fragmentomics-based liquid biopsies in cancer care.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"19 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204005","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 : 2025-09-28DOI: 10.1016/j.ccell.2025.08.005
Johannes Haybaeck, Nicolas Zeller, Monika Julia Wolf, Achim Weber, Ulrich Wagner, Michael Odo Kurrer, Juliane Bremer, Giandomenica Iezzi, Rolf Graf, Pierre-Alain Clavien, Robert Thimme, Hubert Blum, Sergei A. Nedospasov, Kurt Zatloukal, Muhammad Ramzan, Sandra Ciesek, Thomas Pietschmann, Patrice N. Marche, Michael Karin, Manfred Kopf, Mathias Heikenwalder
(Cancer Cell 16, 295–308; October 6, 2009)
（《癌症细胞》16,295 - 308；2009年10月6日）
{"title":"A Lymphotoxin-Driven Pathway to Hepatocellular Carcinoma","authors":"Johannes Haybaeck, Nicolas Zeller, Monika Julia Wolf, Achim Weber, Ulrich Wagner, Michael Odo Kurrer, Juliane Bremer, Giandomenica Iezzi, Rolf Graf, Pierre-Alain Clavien, Robert Thimme, Hubert Blum, Sergei A. Nedospasov, Kurt Zatloukal, Muhammad Ramzan, Sandra Ciesek, Thomas Pietschmann, Patrice N. Marche, Michael Karin, Manfred Kopf, Mathias Heikenwalder","doi":"10.1016/j.ccell.2025.08.005","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.08.005","url":null,"abstract":"(Cancer Cell <em>16</em>, 295–308; October 6, 2009)","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"28 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182868","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 ketogenic diet (KD) is a potential therapeutic strategy for glioma; however, the underlying mechanisms remain unclear. Herein, we first identify that glioma patients exhibit a distinct gut microbial profile characterized by reduced butyrate-producing bacteria abundance, particularly R. faecis, along with decreased butyrate levels. Notably, KD reshapes the gut microbiota especially enriching A. muciniphila in a mucin-2-dependent manner, elevates butyrate production, and activates caspase-3 in microglia. These changes promote an anti-tumor microglial phenotype, ultimately suppressing glioma progression in mice. Crucially, KD’s anti-glioma effect is notably abolished by antibiotics treatment; germ-free condition; or specific depletion of mucin-2, microglia, or microglial caspase-3. Furthermore, butyrate, A. muciniphila, R. faecis, or A. muciniphila plus R. faecis restores KD-induced microglial caspase-3 activation and the anti-tumor phenotype of microglia in antibiotics-treated or germ-free mice. These findings highlight that targeting the gut microbiota by KD or supplementing with butyrate could be an effective strategy for glioma therapy.
{"title":"Ketogenic diet inhibits glioma progression by promoting gut microbiota-derived butyrate production","authors":"Ming-Liang Chen, Ying He, Xun-Hu Dong, Hao-Fei Liu, Ze-Xuan Yan, Xiao-Lu Lu, Qing-Qing Miao, Qing-Ning Zhao, Hang Zhang, Li Luo, Shuai Wang, Jing-Yuan Li, Dong-Fang Xiang, Yong Lin, Tian-Ran Li, Xin-Yue Zhou, Yang-Yang Zhou, Min Mao, Xia Zhang, Hong Wei, Xiu-Wu Bian","doi":"10.1016/j.ccell.2025.09.002","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.09.002","url":null,"abstract":"The ketogenic diet (KD) is a potential therapeutic strategy for glioma; however, the underlying mechanisms remain unclear. Herein, we first identify that glioma patients exhibit a distinct gut microbial profile characterized by reduced butyrate-producing bacteria abundance, particularly <em>R</em>. <em>faecis</em>, along with decreased butyrate levels. Notably, KD reshapes the gut microbiota especially enriching <em>A</em>. <em>muciniphila</em> in a mucin-2-dependent manner, elevates butyrate production, and activates caspase-3 in microglia. These changes promote an anti-tumor microglial phenotype, ultimately suppressing glioma progression in mice. Crucially, KD’s anti-glioma effect is notably abolished by antibiotics treatment; germ-free condition; or specific depletion of mucin-2, microglia, or microglial caspase-3. Furthermore, butyrate, <em>A</em>. <em>muciniphila</em>, <em>R</em>. <em>faecis</em>, or <em>A</em>. <em>muciniphila</em> plus <em>R</em>. <em>faecis</em> restores KD-induced microglial caspase-3 activation and the anti-tumor phenotype of microglia in antibiotics-treated or germ-free mice. These findings highlight that targeting the gut microbiota by KD or supplementing with butyrate could be an effective strategy for glioma therapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"22 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134336","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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