{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T14:00:53Z","timestamp":1790085653718,"version":"4.0.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of hematologic malignancies, yet durable responses remain inconsistent and clinically significant toxicities persist. Emerging evidence identifies the gut microbiota as an extratumoral determinant of CAR-T efficacy, persistence, and toxicity. However, taxonomic signatures associated with clinical outcomes show limited reproducibility and are influenced by antibiotics, geography, diet, and methodological heterogeneity. Building on prior reviews addressing microbiome\u2013CAR-T associations and CAR-T-cell immunometabolism separately, here we synthesize clinical, translational, and preclinical evidence into an integrated, metabolome-centered framework spanning the full CAR-T treatment and manufacturing trajectory. Broad-spectrum antibiotic exposure disrupts microbial metabolic output, depleting short-chain fatty acids, indole derivatives, and other bioactive metabolites, and has been associated with inferior clinical outcomes in several cohorts, although these associations are heterogeneous and may be confounded by baseline disease severity, systemic inflammation, and infection-related factors. Experimental studies further indicate that butyrate, valerate, inosine, indoles, and succinate modulate mitochondrial fitness, memory differentiation, epigenetic programming, cytotoxicity, and exhaustion through interconnected metabolic and receptor-mediated pathways. We propose that the gut microbiota acts as a distributed metabolic organ whose collective output shapes CAR-T-cell fitness and therapeutic response. This framework supports the development of metabolite-based biomarkers and therapeutic strategies, including microbiota-conscious antibiotic stewardship, ecosystem restoration, dietary or metabolite-based interventions, and\n                    <jats:italic>ex vivo<\/jats:italic>\n                    metabolic conditioning during CAR-T manufacturing. Shifting from descriptive microbiome profiling to functional metabolomics may improve both prediction and optimization of CAR-T therapy.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1953443","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:10:40Z","timestamp":1790082640000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Microbiota-derived metabolic priming of CAR-T cell fitness: a translational framework for next-generation cell therapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Simone","family":"Melchiorri","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Padua","place":["Padova, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignazio","family":"Castagliuolo","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Padua","place":["Padova, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15030794","article-title":"CAR-T cell therapy and the gut microbiota","volume":"15","author":"Asokan","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/bs.ircmb.2024.12.015","article-title":"The role of microbiome in CAR-T cell therapy","volume":"394","author":"Abdel-Wahab","year":"2025","journal-title":"Int Rev Cell Mol Biol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s40164-019-0155-8","article-title":"Gut microbiome and CAR-T therapy","volume":"8","author":"Abid","year":"2019","journal-title":"Exp Hematol Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.70120","article-title":"Challenges and solutions to implementation of chimeric antigen receptor therapies in acute myeloid leukemia","volume":"116","author":"Maheswaran","year":"2026","journal-title":"Eur J Haematol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2022.04.015","article-title":"Trust your gut when it comes to driving CARs","volume":"3","author":"Chelvanambi","year":"2022","journal-title":"Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2025.2191","article-title":"The microbiome and cancer: a translational science review","volume":"333","author":"Fernandez","year":"2025","journal-title":"JAMA"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.670286","article-title":"The potential role of the intestinal micromilieu and individual microbes in the immunobiology of chimeric antigen receptor T-cell therapy","volume":"12","author":"Schubert","year":"2021","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14215442","article-title":"Role of CAR T cell metabolism for therapeutic efficacy","volume":"14","author":"Rial Saborido","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1121565","article-title":"Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes","volume":"14","author":"Nanjireddy","year":"2023","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1688995","article-title":"Metabolic reprogramming of CAR T cells: a new frontier in cancer immunotherapy","volume":"16","author":"Frlic","year":"2025","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s40164-024-00535-1","article-title":"Fueling CARs: metabolic strategies to enhance CAR T-cell therapy","volume":"13","author":"Van der Vreken","year":"2024","journal-title":"Exp Hematol Oncol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"6858","DOI":"10.1038\/s41467-023-42634-3","article-title":"Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1\u03b1-mediated glycolytic reprogramming","volume":"14","author":"Wu","year":"2023","journal-title":"Nat Commun"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.016","article-title":"Metabolic competition in the tumor microenvironment is a driver of cancer progression","volume":"162","author":"Chang","year":"2015","journal-title":"Cell"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1269015","article-title":"Learning from the microbes: exploiting the microbiome to enforce T cell immunotherapy","volume":"14","author":"Staudt","year":"2023","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2025.118560","article-title":"Microbiota-derived butyrate potentiates MSLN CAR-T cell therapy by metabolic reprogramming and extracellular matrix remodeling","volume":"192","author":"Chen","year":"2025","journal-title":"BioMed Pharmacother"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2025016858","article-title":"Microbiome and metabolite biomarkers of CAR T-cell therapy outcomes in relapsed\/refractory diffuse large B-cell lymphoma","volume":"10","author":"Yoon","year":"2026","journal-title":"Blood Adv"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01702-9","article-title":"Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy","volume":"28","author":"Smith","year":"2022","journal-title":"Nat Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2024025366","article-title":"Antibiotic-induced loss of gut microbiome metabolic output correlates with clinical responses to CAR T-cell therapy","volume":"145","author":"Prasad","year":"2025","journal-title":"Blood"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02234-6","article-title":"A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy","volume":"29","author":"Stein-Thoeringer","year":"2023","journal-title":"Nat Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines14020298","article-title":"Antibiotic use before CAR-T treatment is associated with inferior outcomes in DLBCL lymphoma patients","volume":"14","author":"Bullegas","year":"2026","journal-title":"Biomedicines"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2024014476","article-title":"Longitudinal analysis of gut microbiome and metabolome correlates of response and toxicity with idecabtagene vicleucel","volume":"9","author":"Saha","year":"2025","journal-title":"Blood Adv"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.22953","article-title":"The impact of antibiotic usage on the efficacy of chemoimmunotherapy is contingent on the source of tumor-reactive T cells","volume":"8","author":"Kuczma","year":"2017","journal-title":"Oncotarget"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-25-1676","article-title":"The potential of the gut microbiota and butyrate to enhance CAR T-cell therapy in non-Hodgkin lymphoma","volume":"32","author":"Garc\u00eda-Vicente","year":"2026","journal-title":"Clin Cancer Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines13092141","article-title":"Gut microbiota dysbiosis and dietary interventions in non-Hodgkin B-cell lymphomas: implications for treatment response","volume":"13","author":"Caserta","year":"2025","journal-title":"Biomedicines"},{"key":"B25","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1016\/j.ymthe.2023.01.012","article-title":"Modulation of the gut microbiota engages antigen cross-presentation to enhance antitumor effects of CAR T cell immunotherapy","volume":"31","author":"Uribe-Herranz","year":"2023","journal-title":"Mol Ther"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.70121","article-title":"Microbiome-based modeling of CAR-T therapy response in lymphoma: insights from shotgun metagenomics sequencing","volume":"116","author":"Hernani","year":"2026","journal-title":"Eur J Haematol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"5313","DOI":"10.1038\/s41467-022-32960-3","article-title":"CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic Malignancies","volume":"13","author":"Hu","year":"2022","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1362133","article-title":"Targeting the gut microbiota to enhance the antitumor efficacy and attenuate the toxicity of CAR-T cell therapy: a new hope","volume":"15","author":"Zhang","year":"2024","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1703146","article-title":"The gut microbiota\u2013brain\u2013CAR T cell axis: a systematic review of gut microbiome modulation and its impact on neurological complications and treatment responses in CAR T cell therapy","volume":"16","author":"Pillai","year":"2026","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1038\/s41419-021-04293-4","article-title":"Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4\/MyD88\/AKT\/NF-\u03baB pathway in pancreatic cancer","volume":"12","author":"Yin","year":"2021","journal-title":"Cell Death Dis"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.20892\/j.issn.2095-3941.2021.0087","article-title":"Focused evaluation of the roles of macrophages in chimeric antigen receptor (CAR) T cell therapy associated cytokine release syndrome","volume":"19","author":"Guo","year":"2021","journal-title":"Cancer Biol Med"},{"key":"B32","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1186\/s12967-025-07646-1","article-title":"Immune effector cell-associated neurotoxicity syndrome following CAR T-cell therapy: a review of recent advances","volume":"24","author":"Fatahichegeni","year":"2025","journal-title":"J Transl Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-1230","article-title":"Gut microbiota modulation through Akkermansia spp. supplementation increases CAR T-cell potency","volume":"15","author":"Marcos-Kovandzic","year":"2025","journal-title":"Cancer Discov"},{"key":"B34","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1158\/2643-3230.BCD-24-0203","article-title":"Microbiota shape metabolic and immune determinants of CAR-T therapy and correlate with outcomes in myeloma","volume":"6","author":"Uribe-Herranz","year":"2025","journal-title":"Blood Cancer Discov"},{"key":"B35","doi-asserted-by":"publisher","first-page":"4077","DOI":"10.1038\/s41467-021-24331-1","article-title":"Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer","volume":"12","author":"Luu","year":"2021","journal-title":"Nat Commun"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2024.101900","article-title":"ARID5A stabilizes indoleamine 2,3-dioxygenase expression and enhances CAR T cell exhaustion in colorectal cancer","volume":"42","author":"Wu","year":"2024","journal-title":"Transl Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019004500","article-title":"Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity","volume":"136","author":"Fultang","year":"2020","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2682-1","article-title":"Cancer SLC43A2 alters T cell methionine metabolism and histone methylation","volume":"585","author":"Bian","year":"2020","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2024.05.017","article-title":"BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism","volume":"32","author":"Yang","year":"2024","journal-title":"Mol Ther"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1638352","article-title":"Interplay between bile acids, gut microbiota, and the tumor immune microenvironment: mechanistic insights and therapeutic strategies","volume":"16","author":"Tong","year":"2025","journal-title":"Front Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S382540","article-title":"Spermidine promotes Nb CAR-T mediated cytotoxicity to lymphoma cells through elevating proliferation and memory","volume":"15","author":"Wang","year":"2022","journal-title":"Onco Targets Ther"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/antib10030025","article-title":"Beyond the lactate paradox: how lactate and acidity impact T cell therapies against cancer","volume":"10","author":"Tu","year":"2021","journal-title":"Antibodies (Basel)"},{"key":"B43","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.omto.2022.03.009","article-title":"CAR T cell therapy and the tumor microenvironment: current challenges and opportunities","volume":"25","author":"Kankeu Fonkoua","year":"2022","journal-title":"Mol Ther Oncolytics"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/sji.13273","article-title":"The role of bone marrow microenvironment on CAR-T efficacy in haematologic Malignancies","volume":"98","author":"Gao","year":"2023","journal-title":"Scand J Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics17121520","article-title":"Rewiring T cell metabolism to enhance CAR T cell function in solid tumor microenvironments","volume":"17","author":"Song","year":"2025","journal-title":"Pharmaceutics"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2023-329543","article-title":"Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1\/Kyn\/AHR axis","volume":"72","author":"Fong","year":"2023","journal-title":"Gut"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1200\/po-24-00753","article-title":"Expanding the therapeutic reach of chimeric antigen receptor T-cells and bispecific T-cell engagers across solid tumors","volume":"9","author":"Gerber","year":"2025","journal-title":"JCO Precis Oncol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.19001","article-title":"Challenges and solutions to superior chimeric antigen receptor-T design and deployment for B-cell lymphomas","volume":"203","author":"Gao","year":"2023","journal-title":"Br J Haematol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(22)00223-X","article-title":"Faecal microbiota transplantation in patients with haematological Malignancies undergoing cellular therapies: from translational research to routine clinical practice","volume":"9","author":"Malard","year":"2022","journal-title":"Lancet Haematol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcyt.2022.05.003","article-title":"Leukapheresis guidance and best practices for optimal chimeric antigen receptor T-cell manufacturing","volume":"24","author":"Qayed","year":"2022","journal-title":"Cytotherapy"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023011992","article-title":"Early predictive factors of failure in autologous CAR T-cell manufacturing and\/or efficacy in hematologic Malignancies","volume":"8","author":"Baguet","year":"2024","journal-title":"Blood Adv"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2025.07.045","article-title":"Advancing CAR-T cell therapy: insights into patient biology, leukapheresis, and cryopreservation","volume":"33","author":"Vega-Blanco","year":"2025","journal-title":"Mol Ther"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2025.02.031","article-title":"Presetting CAR-T cells during ex vivo biomanufacturing","volume":"33","author":"Wang","year":"2025","journal-title":"Mol Ther"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1953443\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:10:41Z","timestamp":1790082641000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1953443\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":53,"alternative-id":["10.3389\/fimmu.2026.1953443"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1953443","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]},"article-number":"1953443"}}