Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-06-20DOI: 10.1016/j.xcrm.2025.102196
Caroline Laheurte, Laura Boullerot, Babacar Ndao, Marine Malfroy, Lise Queiroz, Phillippe Guillaume, Romain Loyon, Evan Seffar, Eleonore Gravelin, Adeline Renaudin, Marion Jacquin, Aurélia Meurisse, Dewi Vernerey, François Ghiringhelli, Yann Godet, Raphael Genolet, Camilla Jandus, Christophe Borg, Olivier Adotévi
{"title":"UCPVax, a CD4 helper peptide vaccine, induces polyfunctional Th1 cells, antibody response, and epitope spreading to improve antitumor immunity.","authors":"Caroline Laheurte, Laura Boullerot, Babacar Ndao, Marine Malfroy, Lise Queiroz, Phillippe Guillaume, Romain Loyon, Evan Seffar, Eleonore Gravelin, Adeline Renaudin, Marion Jacquin, Aurélia Meurisse, Dewi Vernerey, François Ghiringhelli, Yann Godet, Raphael Genolet, Camilla Jandus, Christophe Borg, Olivier Adotévi","doi":"10.1016/j.xcrm.2025.102196","DOIUrl":"10.1016/j.xcrm.2025.102196","url":null,"abstract":"<p><p>The induction of an antitumor CD4<sup>+</sup> T helper response is essential for the efficacy of therapeutic cancer vaccines. However, few vaccines are specifically designed to target CD4<sup>+</sup> T cells in human cancers. Here, we characterize the immune mechanisms of UCPVax, a helper peptide vaccine derived from telomerase. Ex vivo immune profiling of peripheral blood from 60 patients with advanced lung cancer reveals that UCPVax selectively activates CD4<sup>+</sup> T cells in vivo across a broad HLA-DR restriction. The vaccine elicits a synergistic immune triad, including cytokine polyfunctional CD4<sup>+</sup> Th1 cells, epitope spreading, and antibody response, contributing to effective tumor control. Single-cell analysis further demonstrates that UCPVax drives CD4<sup>+</sup> T cells toward effector memory and cytolytic differentiation. Thus, vaccine-induced CD4<sup>+</sup> T cells trigger broad and durable antitumor immunity. These findings highlight UCPVax as an off-the-shelf helper platform to enhance therapeutic cancer vaccine efficacy. This study was registered at ClinicalTrials.gov: NCT02818426.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102196"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339958","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}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-06-19DOI: 10.1016/j.xcrm.2025.102195
Bi-Huei Yang, Alma Gutierrez, Angela Liao, Soheila Shirinbak, Bjoern Gaertner, Mochtar Pribadi, Hui-Yi Chu, Pei-Fang Tsai, Yu-Sheng Eason Lin, David Gonzalez, Wen-I Yeh, Chia-Wei Chang, Ryan Bjordahl, Tom Lee, Martin Hosking, Eigen Peralta, Bahram Valamehr
{"title":"iPSC-derived trimodal T cells engineered with CAR, TCR, and hnCD16 modalities can overcome antigen escape in heterogeneous tumors.","authors":"Bi-Huei Yang, Alma Gutierrez, Angela Liao, Soheila Shirinbak, Bjoern Gaertner, Mochtar Pribadi, Hui-Yi Chu, Pei-Fang Tsai, Yu-Sheng Eason Lin, David Gonzalez, Wen-I Yeh, Chia-Wei Chang, Ryan Bjordahl, Tom Lee, Martin Hosking, Eigen Peralta, Bahram Valamehr","doi":"10.1016/j.xcrm.2025.102195","DOIUrl":"10.1016/j.xcrm.2025.102195","url":null,"abstract":"<p><p>Although chimeric antigen receptor (CAR) T cells have demonstrated therapeutic activity in hematopoietic malignancies, tumor heterogeneity has impeded the efficacy of CAR T cells and their extension into successful solid tumor treatment. To address these challenges, induced pluripotent stem cell (iPSC)-derived T (iT) cells are engineered to uniformly express CAR and T cell receptor (TCR), enabling targeting of both surface and intracellular antigens, respectively, along with a high-affinity, non-cleavable variant of CD16a (hnCD16) to support antibody-dependent cellular cytotoxicity (ADCC) when combined with therapeutic antibodies. Co-expression of each antitumor strategy on engineered iT cells enables independent and antigen-specific targeting across a diverse set of liquid and solid tumors. In heterogeneous tumor models, coactivation of these modalities is required for measurable antitumor efficacy, with activation of all three modalities displaying maximal efficacy. These data highlight the therapeutic potential of an off-the-shelf engineered iPSC-derived trimodal T cell expressing CAR, TCR, and hnCD16 to combat difficult-to-treat heterogeneous tumors.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102195"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336366","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}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-07-07DOI: 10.1016/j.xcrm.2025.102231
Erica Budina, Joseph W Reda, Shijie Cao, Elyse A Watkins, Ani Solanki, Mindy Nguyen, Phillip S Ang, J Emiliano Gómez Medellín, Hye-Rin Chun, Colleen R Foley, Brendan T K Berg, Ha-Na Shim, Kevin Hultgren, Zahra Khosravi, Arjun Dhar, Suzana Gomes, Andrew C Tremain, Ako Ishihara, Jun Ishihara, Jeffrey A Hubbell
{"title":"Activity-attenuated serum albumin-fused interleukin-33 suppresses experimental autoimmune encephalomyelitis.","authors":"Erica Budina, Joseph W Reda, Shijie Cao, Elyse A Watkins, Ani Solanki, Mindy Nguyen, Phillip S Ang, J Emiliano Gómez Medellín, Hye-Rin Chun, Colleen R Foley, Brendan T K Berg, Ha-Na Shim, Kevin Hultgren, Zahra Khosravi, Arjun Dhar, Suzana Gomes, Andrew C Tremain, Ako Ishihara, Jun Ishihara, Jeffrey A Hubbell","doi":"10.1016/j.xcrm.2025.102231","DOIUrl":"10.1016/j.xcrm.2025.102231","url":null,"abstract":"<p><p>Interleukin-33 (IL-33) is an immunoregulatory cytokine that moderately suppresses experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). However, poor pharmacokinetics and toxicity hinder its clinical translation. To address these limitations, we develop an activity-attenuated IL-33 by recombinant fusion to serum albumin (SA). SA-IL-33 exhibits reduced toxicity and prolonged residence in the secondary lymphoid organs (SLOs), sites of T cell priming in autoimmunity, compared to wild-type (WT) IL-33. Prophylactic SA-IL-33 administration prevents EAE with superior efficacy to WT IL-33 and comparable efficacy to fingolimod (FTY720), a Food and Drug Administration (FDA)-approved MS drug. Therapeutic SA-IL-33 treatment also reduces disease severity in both chronic and relapsing-remitting EAE. SA-IL-33 modulates immunity in EAE by suppressing CD45<sup>+</sup> cell infiltration (including myelin-reactive T helper 17 [T<sub>H</sub>17] cells) in the spinal cord, while expanding type 2 immune cells (including type 2 innate lymphoid cells [ILC2s], ST2<sup>+</sup> regulatory T cells [Tregs], T helper 2 [T<sub>H</sub>2] cells, and M2-polarized macrophages) in the SLOs. These findings suggest that SA-IL-33 is a promising therapeutic for neuroinflammatory diseases.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102231"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590564","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}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-06-19DOI: 10.1016/j.xcrm.2025.102193
Liulu Zhang, Lu Yang, Yan Ge, Zhaowen Zhu, Bo Chen, Ciqiu Yang, Hongfei Gao, Mei Yang, Teng Zhu, Kun Wang
{"title":"Neoadjuvant anlotinib/sintilimab plus chemotherapy in triple-negative breast cancer (NeoSACT): Phase 2 trial.","authors":"Liulu Zhang, Lu Yang, Yan Ge, Zhaowen Zhu, Bo Chen, Ciqiu Yang, Hongfei Gao, Mei Yang, Teng Zhu, Kun Wang","doi":"10.1016/j.xcrm.2025.102193","DOIUrl":"10.1016/j.xcrm.2025.102193","url":null,"abstract":"<p><p>Tumor angiogenesis contributes to immune evasion, and vascular normalization enhances immunotherapy response by reshaping the tumor microenvironment. This phase 2 trial evaluates neoadjuvant anlotinib (antiangiogenic), sintilimab (programmed cell death protein 1 [PD-1] inhibitor), and chemotherapy in 29 patients with stage II-III triple-negative breast cancer (TNBC). The primary endpoint, pathological complete response (pCR), is achieved in 69.0% (95% confidence interval [CI]: 49.0%-85.0%), with an 86.2% minimal residual disease (residual cancer burden [RCB] 0 + 1) rate. Notably, programmed death-ligand 1 (PD-L1)-negative patients achieve a 75.0% pCR rate, comparable to PD-L1-positive patients (64.7%). The 2-year event-free survival (EFS) is 92.4%, with 100% EFS in pCR patients. Grade 3/4 adverse events occur in 31.0% of patients, primarily rash and hematologic toxicities. These results demonstrate that combining antiangiogenic therapy with immunotherapy and chemotherapy enhances treatment efficacy, potentially overcoming PD-L1 limitations, and supports further investigation in high-risk TNBC. This trial was registered at ClinicalTrials.gov (NCT04877821).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102193"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336367","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}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-06-25DOI: 10.1016/j.xcrm.2025.102203
Tingyao Li, Shiqun Lin, Zhouyu Guan, Yukun Zhou, Dian Zeng, Zheyuan Wang, Yan Zhou, Pinqi Fang, Shujie Yu, Ruhan Liu, Xiang Chen, Yan-Ran Joyce Wang, Yuwei Lu, Jia Shu, Yiming Qin, Yiting Wu, Yilan Wu, Chan Wu, Shangzhu Zhang, Jie Shen, Huating Li, Tingli Chen, Jin Li, Yih-Chung Tham, Charumathi Sabanayagam, Ying Feng Zheng, Siegfried K Wagner, Pearse A Keane, Tien Yin Wong, Rongping Dai, Bin Sheng
{"title":"A deep learning system for detecting systemic lupus erythematosus from retinal images.","authors":"Tingyao Li, Shiqun Lin, Zhouyu Guan, Yukun Zhou, Dian Zeng, Zheyuan Wang, Yan Zhou, Pinqi Fang, Shujie Yu, Ruhan Liu, Xiang Chen, Yan-Ran Joyce Wang, Yuwei Lu, Jia Shu, Yiming Qin, Yiting Wu, Yilan Wu, Chan Wu, Shangzhu Zhang, Jie Shen, Huating Li, Tingli Chen, Jin Li, Yih-Chung Tham, Charumathi Sabanayagam, Ying Feng Zheng, Siegfried K Wagner, Pearse A Keane, Tien Yin Wong, Rongping Dai, Bin Sheng","doi":"10.1016/j.xcrm.2025.102203","DOIUrl":"10.1016/j.xcrm.2025.102203","url":null,"abstract":"<p><p>Systemic lupus erythematosus (SLE) is a serious autoimmune disorder predominantly affecting women. However, screening for SLE and related complications poses significant challenges globally, due to complex diagnostic criteria and public unawareness. Since SLE-related retinal involvement could provide insights into disease activity and severity, we develop a deep learning system (DeepSLE) to detect SLE and its retinal and kidney complications from retinal images. In multi-ethnic validation datasets comprising 247,718 images from China and UK, DeepSLE achieves areas under the receiver operating characteristic curve of 0.822-0.969 for SLE. Additionally, DeepSLE demonstrates robust performance across subgroups stratified by gender, age, ethnicity, and socioeconomic status. To ensure DeepSLE's explainability, we conduct both qualitative and quantitative analyses. Furthermore, in a prospective reader study, DeepSLE demonstrates higher sensitivities compared with primary care physicians. Altogether, DeepSLE offers digital solutions for detecting SLE and related complications from retinal images, holding potential for future clinical deployment.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102203"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504957","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}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-06-27DOI: 10.1016/j.xcrm.2025.102210
Or-Yam Revach, Angelina M Cicerchia, Ofir Shorer, Claire A Palin, Boryana Petrova, Seth Anderson, Baolin Liu, Joshua Park, Lee Chen, Arnav Mehta, Samuel J Wright, Niamh McNamee, Aya Tal-Mason, Giulia Cattaneo, Payal Tiwari, Hongyan Xie, Johanna M Sweere, Li-Chun Cheng, Natalia Sigal, Elizabeth Enrico, Marisa Miljkovic, Shane A Evans, Ngan Nguyen, Mark E Whidden, Ramji Srinivasan, Matthew H Spitzer, Yi Sun, Tatyana Sharova, Aleigha R Lawless, William A Michaud, Martin Q Rasmussen, Jacy Fang, Jeannette R Brook, Feng Chen, Xinhui Wang, Cristina R Ferrone, Donald P Lawrence, Ryan J Sullivan, David Liu, Uma M Sachdeva, Debattama R Sen, Keith T Flaherty, Robert T Manguso, Lloyd Bod, Manolis Kellis, Genevieve M Boland, Keren Yizhak, Jiekun Yang, Naama Kanarek, Moshe Sade-Feldman, Nir Hacohen, Russell W Jenkins
{"title":"Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants.","authors":"Or-Yam Revach, Angelina M Cicerchia, Ofir Shorer, Claire A Palin, Boryana Petrova, Seth Anderson, Baolin Liu, Joshua Park, Lee Chen, Arnav Mehta, Samuel J Wright, Niamh McNamee, Aya Tal-Mason, Giulia Cattaneo, Payal Tiwari, Hongyan Xie, Johanna M Sweere, Li-Chun Cheng, Natalia Sigal, Elizabeth Enrico, Marisa Miljkovic, Shane A Evans, Ngan Nguyen, Mark E Whidden, Ramji Srinivasan, Matthew H Spitzer, Yi Sun, Tatyana Sharova, Aleigha R Lawless, William A Michaud, Martin Q Rasmussen, Jacy Fang, Jeannette R Brook, Feng Chen, Xinhui Wang, Cristina R Ferrone, Donald P Lawrence, Ryan J Sullivan, David Liu, Uma M Sachdeva, Debattama R Sen, Keith T Flaherty, Robert T Manguso, Lloyd Bod, Manolis Kellis, Genevieve M Boland, Keren Yizhak, Jiekun Yang, Naama Kanarek, Moshe Sade-Feldman, Nir Hacohen, Russell W Jenkins","doi":"10.1016/j.xcrm.2025.102210","DOIUrl":"10.1016/j.xcrm.2025.102210","url":null,"abstract":"<p><p>CD38, an ecto-enzyme involved in NAD<sup>+</sup> catabolism, is highly expressed in exhausted CD8<sup>+</sup> T cells and has emerged as an attractive target to improve response to immune checkpoint blockade (ICB) by blunting T cell exhaustion. However, the precise role(s) and regulation of CD38 in exhausted T cells and the efficacy of CD38-directed therapeutic strategies in human cancer remain incompletely defined. Here, we show that CD38<sup>+</sup>CD8<sup>+</sup> T cells are induced by chronic TCR activation and type I interferon stimulation and confirm their association with ICB resistance in human melanoma. Disrupting CD38 restores cellular NAD<sup>+</sup> pools and improves T cell bioenergetics and effector functions. Targeting CD38 restores ICB sensitivity in a cohort of patient-derived organotypic tumor spheroids from explanted melanoma specimens. These results support further preclinical and clinical evaluation of CD38-directed therapies in melanoma and underscore the importance of NAD<sup>+</sup> as a vital metabolite to enhance those therapies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102210"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511617","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}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-07-07DOI: 10.1016/j.xcrm.2025.102205
Sandra Petrus-Reurer, Winnie Lei, Olivia Tysoe, Maelle Mairesse, Adrian Baez-Ortega, Julia Jones, Thomas Tan, Sylvia Rehakova, Krishnaa T Mahbubani, Cara Brodie, Namshik Han, Inigo Martincorena, Catherine Betts, Ludovic Vallier, Kourosh Saeb-Parsy
{"title":"Immunogenicity of autologous and allogeneic human primary cholangiocyte organoid cellular therapies.","authors":"Sandra Petrus-Reurer, Winnie Lei, Olivia Tysoe, Maelle Mairesse, Adrian Baez-Ortega, Julia Jones, Thomas Tan, Sylvia Rehakova, Krishnaa T Mahbubani, Cara Brodie, Namshik Han, Inigo Martincorena, Catherine Betts, Ludovic Vallier, Kourosh Saeb-Parsy","doi":"10.1016/j.xcrm.2025.102205","DOIUrl":"10.1016/j.xcrm.2025.102205","url":null,"abstract":"<p><p>Primary human cells cultured in long-term expandable 3D organoid format have great promise as potential regenerative cellular therapies, but their immunogenicity has not yet been fully characterized. In this study, we use in vitro co-cultures and in vivo humanized mouse experimental models to examine autologous and allogeneic immune response to human primary cholangiocyte organoids (PCOs) as treatment for bile duct disorders. Our data demonstrate that PCOs upregulate the expression of human leukocyte antigen (HLA)-I and HLA-II in inflammatory conditions. The allogeneic immune response to PCOs is driven by both HLA-I and HLA-II and is substantially ameliorated by donor-recipient HLA matching. While allogeneic cells display evolving stages of immune rejection in vivo, autologous PCOs induce a low-level immune infiltration into the graft site possibly influenced by acquired mutations in culture, cell viability, and culture matrix. Our findings have important implications for the design and clinical translation of autologous and allogeneic organoid cellular therapies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102205"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590565","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}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-07-08DOI: 10.1016/j.xcrm.2025.102233
Florian Dilasser, Lindsay Rose, Agnès Quemener, Yann Ferrandez, Dorian Hassoun, Morgane Rousselle, Hugo Bergereau, Séverine Marionneau Lambot, Luciano E Anselmino, Camille Trouillet, Gwennan Andre, Mike Maillasson, Mikael Croyal, Matthieu Riviere, Didier Dubreuil, Sylvain Collet, Frédérique Souaze, Mario Campone, Anne Patsouris, Erwan Mortier, Mauricio Menacho Marquez, Philippe Juin, Jacques Lebreton, Arnaud Tessier, Jacqueline Cherfils, Gervaise Loirand, Vincent Sauzeau
{"title":"A Rac-specific competitive inhibitor of guanine nucleotide binding reduces metastasis in triple-negative breast cancer.","authors":"Florian Dilasser, Lindsay Rose, Agnès Quemener, Yann Ferrandez, Dorian Hassoun, Morgane Rousselle, Hugo Bergereau, Séverine Marionneau Lambot, Luciano E Anselmino, Camille Trouillet, Gwennan Andre, Mike Maillasson, Mikael Croyal, Matthieu Riviere, Didier Dubreuil, Sylvain Collet, Frédérique Souaze, Mario Campone, Anne Patsouris, Erwan Mortier, Mauricio Menacho Marquez, Philippe Juin, Jacques Lebreton, Arnaud Tessier, Jacqueline Cherfils, Gervaise Loirand, Vincent Sauzeau","doi":"10.1016/j.xcrm.2025.102233","DOIUrl":"10.1016/j.xcrm.2025.102233","url":null,"abstract":"<p><p>The dysregulation of RAC1 activity is associated with neoplastic transformation, metastasis, and poor prognosis in several cancers. Here, we discover in silico a series of RAC1 inhibitors. The most potent of them, A41, specifically inhibits RAC1 with an original mechanism of action. We characterize A41 as a reversible inhibitor that competes with guanine nucleotide binding specifically on RAC proteins. A41 efficiently blocks RAC1 activity and RAC1-dependent cell functions including cell adhesion and migration. Chronic administration of A41 exhibits anti-metastatic effects in mouse models of triple-negative breast cancer, leading to an increase in the survival rate. Our findings suggest that this molecule, A41, could be a promising and powerful therapeutic agent for limiting invasive cancers in patients.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102233"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599521","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":"Interferon-responsive HEVs drive tumor tertiary lymphoid structure formation and predict immunotherapy response in nasopharyngeal carcinoma.","authors":"Shang-Xin Liu, Tao-Wei Wu, Dong-Hua Luo, Le-Le Zhang, Lu Zhou, Yi-Ling Luo, Wen-Ting Du, Ting-Ting Huang, Sizun Jiang, Zhe Zhang, Ping Han, Mu-Sheng Zeng, Qian Zhong","doi":"10.1016/j.xcrm.2025.102200","DOIUrl":"10.1016/j.xcrm.2025.102200","url":null,"abstract":"<p><p>The outcome of immune checkpoint blockade (ICB) therapy largely hinges on the antitumor immunity of tertiary lymphoid structures (TLSs), but drivers of tumor TLS formation remain exclusive. By integrating spatial transcriptomics and a pan-cancer single-cell atlas, we reveal the characteristics of TLSs in nasopharyngeal carcinoma (NPC) and identify a subset of interferon-responsive high endothelial venules (IFN-HEVs) that links to the emergence of tumor-specific chemokines, especially CXCL9. Functionally, CXCL9-secreting IFN-HEVs are associated with the recruitment of CXCR3<sup>+</sup>CD4<sup>+</sup> T cells into TLSs. IFN-HEV-related phenotypes are strongly correlated with prolonged survival and enhanced ICB responsiveness. Leveraging these phenotypes, we develop a pretreatment CXCL9-TLS response-predictive scoring system (CTRscore), which robustly forecasts ICB therapeutic outcomes in three independent NPC cohorts. Our study provides biological and functional insights into the IFN-HEVs in tumor TLSs, highlighting their potential role in the development of biomarkers and predictors for the success of ICB therapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102200"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339946","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}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-06-26DOI: 10.1016/j.xcrm.2025.102204
Sara Labiano, Javier Marco-Sanz, Iker Ausejo-Mauleon, Virginia Laspidea, Reyes Hernández-Osuna, Marc Garcia-Moure, Daniel de la Nava, Sara Nuin, Marisol Gonzalez-Huarriz, Timothy N Phoenix, Ibon Tamayo, Marta Zalacain, Andrea Lacalle, Lucía Marrodan, Montserrat Puigdelloses, Irati Hervás-Corpión, Maria C Ochoa, Noelia Casares, Oren J Becher, Candelaria Gomez-Manzano, Juan Fueyo, Jaime Gallego Perez-Larraya, Ana Patiño-Garcia, Marta M Alonso
{"title":"Targeting the CD40 costimulatory receptor to improve virotherapy efficacy in diffuse midline gliomas.","authors":"Sara Labiano, Javier Marco-Sanz, Iker Ausejo-Mauleon, Virginia Laspidea, Reyes Hernández-Osuna, Marc Garcia-Moure, Daniel de la Nava, Sara Nuin, Marisol Gonzalez-Huarriz, Timothy N Phoenix, Ibon Tamayo, Marta Zalacain, Andrea Lacalle, Lucía Marrodan, Montserrat Puigdelloses, Irati Hervás-Corpión, Maria C Ochoa, Noelia Casares, Oren J Becher, Candelaria Gomez-Manzano, Juan Fueyo, Jaime Gallego Perez-Larraya, Ana Patiño-Garcia, Marta M Alonso","doi":"10.1016/j.xcrm.2025.102204","DOIUrl":"10.1016/j.xcrm.2025.102204","url":null,"abstract":"<p><p>Diffuse midline glioma (DMG) is a devastating pediatric brain tumor. The oncolytic adenovirus Delta-24-RGD has shown promising efficacy and safety in DMG patients but is not yet curative. Thus, we hypothesized that activating dendritic cells (DCs) through the CD40 costimulatory receptor could increase antigen presentation and enhance the anti-tumor effect of the virus, resulting in long-term responses. This study shows that the intratumoral co-administration of Delta-24-RGD and a CD40 agonistic antibody is well tolerated and induces long-term anti-tumor immunity, including complete responses (up to 40%) in DMG preclinical models. Mechanistic studies revealed that this therapy increased tumor-proliferating T lymphocytes and proinflammatory myeloid cells, including mature DCs with superior tumor antigen uptake capacity. Moreover, the lack of cross-presenting DCs and the prevention of DC recruitment into the tumor abolish the Delta-24-RGD+anti-CD40 anti-DMG effect. This approach shows potential for combining virotherapy with activating antigen-presenting cells in these challenging tumors.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102204"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511618","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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