{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:29:01Z","timestamp":1790724541018,"version":"4.1.0"},"reference-count":167,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"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>Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic cancers but encounters challenges, including severe treatment-related toxicities, a highly suppressive tumor microenvironment (TME), limited long-term persistence, and poor trafficking\/infiltration into solid tumors. This review outlines recent genetic engineering strategies to address these issues and enhance the safety, durability, and efficacy of CAR-T cell therapy. To reduce cytokine release syndrome and neurotoxicity, methods such as affinity-tuned and humanized scFvs, hinge\/TM optimization, and ITAM calibration have been developed, along with programmable \u201cswitch-off\u201d and \u201cswitch-on\u201d systems that include suicide genes, antibody-bridging switches, and optogenetic or hypoxia-gated circuits. TME remodeling strategies utilize nanomaterials for targeted cytokine delivery, cell-surface \u201cbackpack\u201d systems, and engineered oncolytic viruses that release cytokines or checkpoint-blocking agents. For durability and resistance to exhaustion, precise genome engineering techniques, including CRISPR-based editing and multiplexed shRNA platforms, were employed to target inhibitory receptors and exhaustion-driving transcriptional programs. Additionally, chemokine-receptor engineering and local biomaterial-based delivery systems are discussed as ways to enhance CAR-T trafficking and intratumoral persistence. These innovations collectively point toward integrated, patient-specific CAR-T platforms that incorporate safety controls, metabolic and transcriptional flexibility, and enhanced trafficking through the TME to broaden clinical use.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1813730","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:39:42Z","timestamp":1779255582000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Advanced strategies to enhance the safety, persistence, and efficacy of CAR-T cells in solid tumors"],"prefix":"10.3389","volume":"17","author":[{"given":"Iqra","family":"Ajmal","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University","place":["Dongguan, Guangdong, China"]},{"name":"Shanghai Key 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