{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:45:39Z","timestamp":1791981939279,"version":"4.4.0"},"reference-count":86,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"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>CAR T-cell therapy has delivered durable remissions in several hematologic cancers, yet activity in solid tumors and extension to immune-mediated diseases remain constrained by recurring failure modes: imperfect antigen specificity, inadequate trafficking, progressive dysfunction under chronic stimulation, and toxic inflammatory syndromes. Early reports of CAR-based immune \u201cresets\u201d in refractory autoimmune disease amplify both promise and stakes, because acceptable risk is lower than in cancer and \u201con-target\u201d effects may still be clinically unacceptable if they create long-term immunodeficiency. This review treats CAR T optimization as multi-layer reprogramming across genetic circuitry, epigenetic state, metabolism, and the tissue microenvironment. We argue that many celebrated single-layer upgrades (stronger signaling, checkpoint deletion, constitutive cytokine armoring) often trade one failure mode for another. Instead, the most credible path to simultaneously improving efficacy and safety is disciplined, failure-mode\u2013driven design: (i) programmable antigen logic and titratable activation to reduce off-tissue damage; (ii) epigenetic programming that preserves renewable functional states without removing essential restraints; (iii) metabolic rewiring evaluated under physiologic stress conditions; and (iv) microenvironment-aware strategies that prioritize access and local control over brute-force potency.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1806459","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T05:35:03Z","timestamp":1775540103000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Reprogramming CAR T cells across genetic, epigenetic, metabolic and microenvironmental axes to improve efficacy and safety in cancer and autoimmune 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