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Given that most CAR constructs have been optimized for \u03b1\u03b2 T cells, we hypothesized that distinct T-cell types may require tailored CAR architectures to achieve optimal function. To test this hypothesis, we conducted a systematic comparative analysis of \u03b3\u03b4 and \u03b1\u03b2 T cells transduced with a second-generation PSCA-targeting CAR (PSCA-8t28z). We found that although \u03b3\u03b4 and \u03b1\u03b2 CAR-T cells exhibit comparable levels of cytotoxicity, they differ phenotypically. Through a system-level phosphoproteomic analysis, we identified 307 phosphosites whose abundance differed between \u03b3\u03b4 and \u03b1\u03b2 CAR-T cells. Pathway enrichment analysis placed glycolysis\/gluconeogenesis and TCR signaling within the top significantly overrepresented signaling networks. The results of functional validation studies confirmed that \u03b3\u03b4 CAR-T cells have lower glycolytic and oxidative phosphorylation capacity than \u03b1\u03b2-CAR-T cells do and weaker activation of activator\u00a0protein 1 (AP-1). Notably, we identified thioredoxin-interacting protein\u00a0(TXNIP) as a potential actionable target to enhance \u03b3\u03b4 CAR-T-cell metabolism. Finally, we designed a new synthetic costimulatory receptor that potentiates AP-1 activation, resulting in improved in vivo persistence. These results highlight the fundamental biological differences between \u03b3\u03b4 and \u03b1\u03b2 T cells and support the development of cell type-specific receptor engineering strategies to maximize \u03b3\u03b4 CAR-T-cell function and therapeutic benefit.<\/jats:p>","DOI":"10.1038\/s41423-026-01475-y","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:05:39Z","timestamp":1790733939000},"page":"1441-1456","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CAR signaling instructs divergent metabolic reprogramming and functional fates in \u03b1\u03b2 and \u03b3\u03b4 T cells"],"prefix":"10.1038","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2840-758X","authenticated-orcid":false,"given":"Xiomar E.","family":"Bustos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"Tordesillas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3220-5395","authenticated-orcid":false,"given":"Elena","family":"Martinez Planes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7563-3350","authenticated-orcid":false,"given":"Miguel G.","family":"Fontela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Snedal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata Ariza Marques","family":"Rossetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Izumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3818-1762","authenticated-orcid":false,"given":"John M.","family":"Koomen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Welsh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Hwu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2571-0215","authenticated-orcid":false,"given":"Daniel","family":"Abate-Daga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"1475_CR1","volume":"14","author":"CQ Wang","year":"2023","unstructured":"Wang CQ, Lim PY, Tan AH. 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