Science Immunology最新文献

{"title":"An autoinflammatory CDC42 variant M45L demonstrates the mechanism of pyrin inflammasome activation","authors":"Shouya Feng,&nbsp;Thomas Reygaerts,&nbsp;Klara Kong,&nbsp;Matthew C. Wierzbowski,&nbsp;Dhanya Lakshmi Narayanan,&nbsp;Paul J. Baker,&nbsp;Imogen Bishop,&nbsp;Maria Zyulina,&nbsp;Katherine Rosevear,&nbsp;Madeline L. Cleveland,&nbsp;Tim C. Hewitt,&nbsp;T. Daniel Andrews,&nbsp;Davide Randazzo,&nbsp;Peter J. Steinbach,&nbsp;Jae Jin Chae,&nbsp;Hyeonji Kim,&nbsp;Daniel L. Kastner,&nbsp;William D. Renton,&nbsp;Samar Ojaimi,&nbsp;Wonyong Lee,&nbsp;Seth L. Masters","doi":"10.1126/sciimmunol.adz8733","DOIUrl":"10.1126/sciimmunol.adz8733","url":null,"abstract":"<div >CDC42 is an evolutionarily conserved guanosine triphosphatase (GTPase) regulating critical cellular and immune processes. Variants in CDC42 therefore cause a spectrum of developmental phenotypes, including hematological and immunological symptoms. Here, we identify a previously unrecognized autoinflammatory condition caused by CDC42^{Met45→Leu(M45L)}. We confirm the pathogenicity of CDC42^M45L given that it promotes pyrin inflammasome activation, consistent with highly elevated circulating interleukin-18 (IL-18) in all affected individuals. Coimmunoprecipitation demonstrates that CDC42 interacts with the PYD and B30.2 domains of pyrin. The B30.2 interaction is greatly enhanced by CDC42^M45L. Models show that CDC42 methionine-45 sits in a hydrophobic cleft of the pyrin B30.2 domain, and substitution with a negatively charged residue prevents colocalization between CDC42 and pyrin. This study supports a model whereby CDC42 nucleates pyrin via the B30.2 domain, after which a threshold is reached to liberate the PYD for inflammasome activation. Blocking the inflammasome-associated cytokine IL-1 was therapeutically effective when tested against this autoinflammatory CDC42^M45L endotype.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 122","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148687815","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}

{"title":"An N-terminal CDC42 T43I variant reveals the mechanism of pyrin inflammasome activation","authors":"Mariko Aoki,&nbsp;Alberto Iannuzzo,&nbsp;Philippe Mertz,&nbsp;Shouya Feng,&nbsp;Naoya Iwata,&nbsp;Chiara Perugini,&nbsp;Naomi Tsuchida,&nbsp;Rana El Masri,&nbsp;Yoshihiko Kuchitsu,&nbsp;Rachida Tacine,&nbsp;Simona Coppola,&nbsp;Hirofumi Shibata,&nbsp;Margaux Cescato,&nbsp;Masahiko Nishitani-Isa,&nbsp;Alexandre Terré,&nbsp;Yuri Kawasaki,&nbsp;Sarah Dalmon,&nbsp;Kenichi Nishimura,&nbsp;Flora Magnotti,&nbsp;Satoko Miyatake,&nbsp;Marc André,&nbsp;Keisuke Hamada,&nbsp;Jonathan London,&nbsp;Kazushi Izawa,&nbsp;Akira Niwa,&nbsp;Nobuhiko Okamoto,&nbsp;Kazuhiro Ogata,&nbsp;Masashi Nishikawa,&nbsp;Erika Zara,&nbsp;Megumu K. Saito,&nbsp;Marco Tartaglia,&nbsp;Shuichi Ito,&nbsp;Mathieu P. Rodero,&nbsp;Koh-ichi Nagata,&nbsp;Asma Smahi,&nbsp;Naomichi Matsumoto,&nbsp;Laurent Le Corre,&nbsp;Junko Takita,&nbsp;Guilaine Boursier,&nbsp;Atsushi Hijikata,&nbsp;Thomas Henry,&nbsp;Tomohiko Taguchi,&nbsp;Véronique Hentgen,&nbsp;Sophie Georgin-Lavialle,&nbsp;Yoshitaka Honda,&nbsp;Seth L. Masters,&nbsp;Takahiro Yasumi,&nbsp;Jérôme Delon","doi":"10.1126/sciimmunol.aea0515","DOIUrl":"10.1126/sciimmunol.aea0515","url":null,"abstract":"<div >Heterozygous carboxyl-terminal variants in the RHO guanosine triphosphatase (GTPase) CDC42 are known to cause severe autoinflammatory syndromes. Here, we identified a heterozygous amino-terminal p.T43I (Thr⁴³→Ile) CDC42 variant in patients with autoinflammation and uncovered a molecular link between CDC42 and the inflammasome sensor pyrin, mutated in the hereditary autoinflammatory syndrome familial Mediterranean fever. We demonstrate that the region surrounding residue T43 of CDC42 interacts with the carboxyl-terminal B30.2 domain of pyrin and regulates its localization and activation. The p.T43I substitution strengthens the CDC42-pyrin interaction through additional van der Waals interactions, leading to increased pyrin inflammasome activation, as evidenced by increased ASC (apoptosis-associated speck-like protein containing a caspase activating and recruitment domain) speck formation, enhanced pyroptosis, and excessive interleukin-1β (IL-1β) and IL-18 production. These findings identify CDC42 as a pyrin ligand and provide critical insights into the role of the pyrin B30.2 domain in inflammasome activation, suggesting dual regulation of pyrin by two RHO family GTPases, RHOA and CDC42.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 122","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148687814","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}

{"title":"Misfirin’ pyrin","authors":"Fiachra Humphries","doi":"10.1126/sciimmunol.aei8902","DOIUrl":"10.1126/sciimmunol.aei8902","url":null,"abstract":"<div >Three studies identify CDC42 as binding partner of the pyrin B30.2 domain, establishing a previously unrecognized mechanism regulating pyrin inflammasome activation (see related Research Articles by Aoki <i>et al.</i>, Feng <i>et al.</i>, and Iwata <i>et al.</i>)</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 122","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688030","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}

{"title":"Dynamic expression of IL-21 in effector CD8 T cells helps control chronic infections","authors":"Zixuan Zhao,&nbsp;Han Feng,&nbsp;Xiaohong Zhao,&nbsp;Bowen Xie,&nbsp;Tian Xie,&nbsp;Qinli Sun,&nbsp;Yongzhen Chen,&nbsp;Kun Wei,&nbsp;Birui Pan,&nbsp;Peng Wei,&nbsp;Xuan Zhong,&nbsp;Lei Yuan,&nbsp;Xue Bai,&nbsp;Xiaohu Wang,&nbsp;Chen Dong","doi":"10.1126/sciimmunol.aec5171","DOIUrl":"10.1126/sciimmunol.aec5171","url":null,"abstract":"<div >CD8 T cells are critical players in immune responses against pathogens. Interleukin-21 (IL-21) is predominantly produced by CD4 T cells and exerts multifaceted effects on CD8 T cell regulation and function. Using <i>Il21</i>-reporter and <i>Il21</i>–fate mapping mice, we report that a subpopulation of activated CD8 T cells also produces IL-21 in the context of lymphocytic choriomeningitis virus (LCMV) infection. During the early effector phase of both acute and chronic infections, IL-21–expressing CD8 T cells exhibit substantial proliferative and cytotoxic capacities, with higher levels of interferon-γ (IFN-γ) and granzyme B (GZMB) compared with IL-21⁻ counterparts. Moreover, CD8 T cell–derived IL-21 played a critical protective role in chronic, but not acute, infection. IL-21 expression in CD8 T cells appeared to be largely restricted to exhausted progenitor T cells during the exhaustion phase of chronic infection. These findings identify IL-21–expressing CD8 T cells as pivotal players in the control of chronic infection.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 121","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148628749","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}

{"title":"Two differentiation pathways generate large peritoneal macrophages with one replenishing mesothelial border macrophages","authors":"Jichang Han,&nbsp;Alexandre Gallerand,&nbsp;Rachel L. Mintz,&nbsp;Jing Chen,&nbsp;Feiya Ou,&nbsp;Shuai Gao,&nbsp;Daniel D. Lee,&nbsp;Mandy M. Chan,&nbsp;Michael T. Harmon,&nbsp;Xue Lin,&nbsp;Bhama Ramkhelawon,&nbsp;Christopher G. Huckstep,&nbsp;Michael R. Strickland,&nbsp;Tiantian Liu,&nbsp;Kory J. Lavine,&nbsp;Joel D. Schilling,&nbsp;S. Celeste Morley,&nbsp;Bernd H. Zinselmeyer,&nbsp;Kenneth M. Murphy,&nbsp;Gwendalyn J. Randolph","doi":"10.1126/sciimmunol.aeg8653","DOIUrl":"10.1126/sciimmunol.aeg8653","url":null,"abstract":"<div >Peritoneal cavity fluid and mesothelial surfaces host distinct resident macrophage populations, among which include the well-described Gata6⁺ large cavity macrophages (LCMs) in peritoneal fluid. Here, we reveal that LCMs arise from two separable differentiation pathways. In the quantitatively minor pathway, monocytes gave rise to LYVE1⁺ LCMs but few Gata6⁺ LCMs. This pathway did not require the transcription factor Gata6 but was severely impaired in mice bearing three mutations in the −165 kb <i>Zeb2</i> enhancer (<i>Zeb2</i>^TM) with impaired monocyte development. The second, dominant pathway supported Gata6-dependent LCMs and was intact in <i>Zeb2</i>^TM mice, even when turnover was enforced by irradiation, and was supported by adoptive transfer of a specialized LCM intermediate expressing Gata6 before the residency marker TIMD4. Functionally, the quantitatively minor LCM pathway distinctly surveilled the mesothelium, replenishing mesothelial border macrophages upon encountering an open niche. Thus, beyond embryonic versus adult hematopoietic paradigms, LCMs with overlapping and distinct phenotypes arise from two pathways linked to divergent fates.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 121","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148628750","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}

{"title":"Dynamic regulation of lysine and arginine metabolism promotes immune evasion by limiting T cell function in cancer","authors":"Weiwei Yu,&nbsp;Ruya Sun,&nbsp;Xiaoyang Lu,&nbsp;Qiqi Deng,&nbsp;Heng Zhang,&nbsp;Sheng Chen,&nbsp;Siqi Dai,&nbsp;Tianyi Hu,&nbsp;Xiangyuan Li,&nbsp;Yidong Yang,&nbsp;Lihao Chen,&nbsp;Zhexu Chi,&nbsp;Jian Zhang,&nbsp;Siwen Zhang,&nbsp;Yiyi Zhu,&nbsp;Dehang Yang,&nbsp;Qianzhou Yu,&nbsp;Zhen Wang,&nbsp;Quanquan Wang,&nbsp;Fan Yang,&nbsp;Qian Xiao,&nbsp;Kefeng Ding,&nbsp;Di Wang","doi":"10.1126/sciimmunol.aeb7315","DOIUrl":"10.1126/sciimmunol.aeb7315","url":null,"abstract":"<div >Tumor cells promote metabolic dysregulation of immune cells by controlling the metabolic landscape of the tumor microenvironment. It is unclear whether tumors restrict specific nutrients to drive rapid growth and immune evasion in addition to the overconsumption of nutrients to support anabolism. We identified that up-regulation of solute carrier family 7 member 1 (SLC7A1) increased arginine utilization and promoted tumor growth, whereas down-regulation of SLC7A2 decreased lysine catabolism to support immune evasion. Repression of lysine catabolism in tumor cells reduced glutaconic acid (GC), a medium-chain acyl-CoA dehydrogenase–dependent lysine catabolite that has immunostimulatory effects on antitumor CD8 T cells. GC modified pyruvate kinase M2 (PKM2) through posttranslational glutaconylation at key lysine residues Lys³³⁶ (K336) and K337. This modification reinforced PKM2 dimers, transcriptionally driving metabolic reprogramming and reinvigorating antitumor CD8 T cells. Our study highlights an amino acid trade-off that dynamically optimizes the metabolic preferences of tumors to promote proliferation and immune evasion.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 121","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148565070","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}

{"title":"Genomic correlates of clinical CAR T cell activity","authors":"Mark B. Leick,&nbsp;Baihe Sun,&nbsp;Filippo Birocchi,&nbsp;Kathleen M. E. Gallagher,&nbsp;Alexandra Bratt,&nbsp;Seunghun Han,&nbsp;Grace Martin,&nbsp;Harrison J. Silva,&nbsp;Rebecca C. Larson,&nbsp;Tyler M. Chinsky,&nbsp;Hoyin Chu,&nbsp;Christopher R. Reilly,&nbsp;Michael C. Kann,&nbsp;Bryan D. Choi,&nbsp;Sabrina Camp,&nbsp;Riaz Gillani,&nbsp;Merle Phillips,&nbsp;Tamina Kienka,&nbsp;Stefanie R. Bailey,&nbsp;Charlotte E. Graham,&nbsp;Max Jan,&nbsp;Nicholas S. Moore,&nbsp;Nora Horick,&nbsp;Justin Budka,&nbsp;Simone Filosto,&nbsp;Chad M. Williams,&nbsp;Ali Hosseini Rad,&nbsp;Rhine R. Shen,&nbsp;Eliezer Van Allen,&nbsp;Saud AlDubayan,&nbsp;Marcela V. Maus","doi":"10.1126/sciimmunol.aef4134","DOIUrl":"10.1126/sciimmunol.aef4134","url":null,"abstract":"<div >Germline variants influence immune checkpoint inhibitor responses, but their role in engineered immune cell therapies, such as chimeric antigen receptor T cells (CAR T cells), remains unclear. We integrated whole germline sequencing from patients with lymphoma treated with axicabtagene ciloleucel CAR T cell products in the ZUMA-1 and ZUMA-7 clinical trials with detailed biomarker and functional analyses to identify variants influencing clinical toxicity and pharmacokinetics. Putative deleterious variants in <i>STXBP2</i> (<i>syntaxin binding protein 2</i>) were enriched among patients with toxicity in ZUMA-1, although not confirmed in ZUMA-7. Mechanistically, <i>STXBP2-</i>deficient or variant-expressing T cells triggered increased inflammatory cytokine production and macrophage activation. Conversely, variants in <i>ADAMTSL3</i>, a TGFβ (transforming growth factor–β) signaling regulator, correlated with protection from toxicity across both trials. Furthermore, variants in <i>PTPN22</i>, a negative regulator of T cell receptor signaling, strongly associated with enhanced CAR T cell expansion, a key determinant of efficacy. Together, these findings demonstrate that germline genetics shape the safety and activity of engineered immune cell therapies, affecting future design and patient management.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 121","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.aef4134","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148565069","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}

{"title":"Macrophage-derived oxysterols organize T helper 2 cells to suppress type 1 inflammation during pulmonary fungal infection","authors":"Yufan Zheng,&nbsp;Hannah E. Dobson,&nbsp;Makheni Jean Pierre,&nbsp;Lillian B. LeBlanc,&nbsp;Chinaemerem U. Onyishi,&nbsp;Dominic P. Golec,&nbsp;Nathan Carrillo,&nbsp;Anshu Deewan,&nbsp;Claudia A. Rivera,&nbsp;Eduard Ansaldo,&nbsp;Pamela L. Schwartzberg,&nbsp;Eric V. Dang","doi":"10.1126/sciimmunol.aee0990","DOIUrl":"10.1126/sciimmunol.aee0990","url":null,"abstract":"<div >Effective pulmonary immunity requires the precise spatial organization of immune cells, yet the mechanisms guiding their intratissue positioning during inflammation remain unclear. Here, we identify a cholesterol-derived chemotactic axis that spatially organizes T helper 2 (T_H2) cells during fungal-induced pulmonary type 2 inflammation. Inflammation-expanded macrophages expressing cholesterol-25-hydroxylase (CH25H) produced 25-hydroxycholesterol, which was converted into the oxysterol 7α,25-dihydroxycholesterol to attract GPR183-expressing T_H2 cells into infectious lesions. This T_H2 cell positioning suppressed interferon-γ responsiveness in inflammatory Ly6C⁺ macrophages, promoting fungal persistence. Disruption of this axis via T_H2-specific GPR183 deletion restored type 1 macrophage activation and enhanced fungal clearance. Our findings reveal a macrophage-driven, metabolite-based mechanism of immunosuppressive cell positioning in inflamed lung tissue.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 121","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.aee0990","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148460182","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}

{"title":"Mucosal tissue cues shape B cell memory through the IgA BCR","authors":"Maria Pia Holgado,&nbsp;Samuel Origlio,&nbsp;Lucas Bertoia,&nbsp;Myriam Moussa,&nbsp;Apurwa Trivedi,&nbsp;Frederic Fiore,&nbsp;Ana Zarubica,&nbsp;Emma Slack,&nbsp;Michelle A. Linterman,&nbsp;Michel Cogné,&nbsp;Claude Gregoire,&nbsp;Mauro Gaya","doi":"10.1126/sciimmunol.adv1149","DOIUrl":"10.1126/sciimmunol.adv1149","url":null,"abstract":"<div >B cells generate plasma cells (PCs) and memory B cells (MBCs) to combat recurrent pathogens. B cell receptor (BCR) affinity dictates fate decisions in response to model antigens, but the factors regulating B cell fate during infection remain unknown. Here, we used respiratory and gastrointestinal infection models to study B cell selection across barrier tissues in mice. Memory selection was governed by tissue-specific cues: Selection in the lung was skewed toward MBCs, whereas the gut favored PC entry, even in response to the same pathogen. Divergence was linked to differential BCR isotype usage across barrier tissues rather than differential affinity maturation. In the gut, the commensal-induced TGF-β–rich milieu promoted class-switching to IgA, which skewed selection toward PCs, a process that was counteracted by the IgA cytosolic tail domain. Thus, mucosal B cell selection integrates tissue-specific cues by relying on BCR isotype usage, with implications for nasal and oral vaccine development.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 121","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adv1149","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148460183","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}

{"title":"The efficacy of immunotherapy in glioma requires distal B cell responses in tumor-draining lymph nodes","authors":"Yumin Kim,&nbsp;In Kang,&nbsp;Byeong Hoon Kang,&nbsp;Won Hyung Park,&nbsp;Chae Won Kim,&nbsp;Hyun-Jin Kim,&nbsp;Jeongwoo La,&nbsp;Myoung Seung Kwon,&nbsp;Sang Hee Park,&nbsp;Seo Hyeon Im,&nbsp;Hyeon Cheol Kim,&nbsp;Keun Bon Ku,&nbsp;Minji Kim,&nbsp;Ji Eun Oh,&nbsp;Heung Kyu Lee","doi":"10.1126/sciimmunol.adz2494","DOIUrl":"10.1126/sciimmunol.adz2494","url":null,"abstract":"<div >Humoral immunity, mediated by B cells that mature in germinal centers in lymph nodes (LNs), is essential for adaptive immune responses, but its role in antitumor immunity and responses to immunotherapy remain unclear. Here, we show that activation of B cells in tumor-draining deep cervical LNs (dcLNs) is necessary for the efficacy of CTLA-4 (cytotoxic T lymphocyte–associated protein 4) immune checkpoint blockade in glioma in vivo. Anti–CTLA-4 therapy enhanced T follicular helper cell (T_FH cell) expansion in dcLNs, leading to germinal center B cell responses, immunoglobulin G (IgG) class switching, and the generation of glioma-reactive antibodies. Glioma-bearing mice lacking antibody-secreting cells did not benefit from CTLA-4 blockade. Distally secreted IgG accumulated in the tumor microenvironment and promoted glioma cell phagocytosis in vivo. These findings define a B cell–dependent mechanism underlying CTLA-4–mediated control of glioma and provide a conceptual framework for future therapeutic strategies in tumor.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 121","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148414712","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}