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Our prior genome-wide CRISPR\/Cas9 screening revealed that the loss of CD58, a crucial intrinsic resistance factor in tumors, resulted in insufficient immune synapse formation and impaired CAR T-cell activation and cytotoxicity. However, the specific signaling pathway and transcriptional changes associated with CAR T-cell dysfunction have not been addressed. Here, we revealed that AP-1-mediated activation was attenuated in CAR T cells impaired by tumor CD58 loss, driving a decrease in mitochondrial biogenesis, metabolic kinetic impairment, mitochondrial membrane potential loss and ROS accumulation. Moreover, this AP-1 attenuation triggered death receptor-independent apoptosis through the intrinsic mitochondrial pathway. In seeking therapeutic strategies, we pharmacologically and genetically blocked three distinct inhibitory phosphatases positioned upstream of AP-1 signaling. Multifaceted validation has demonstrated that dual specificity phosphatase 6 (DUSP6) blockade is an effective approach to supplement AP-1 signaling while notably reducing CAR T-apoptosis and enhancing mitochondrial fitness, proliferation and long-term cytotoxicity. The transcriptomic profiles of DUSP6-ablated CAR T cells revealed markedly upregulated T-cell activation signatures and enriched metabolic pathways. Clinically, bulk and single-cell RNA-seq analyses revealed that DUSP6 was downregulated in patients who responded to T-cell-based immunotherapy, implying its relevance to patient outcomes. Our findings repositioned CD58 not merely as an immune synapse component but also a metabolic checkpoint in CAR T-cell biology, the loss of which triggers AP-1-dependent mitochondrial derangement and creates a permissive landscape for intrinsic apoptosis, which can be ameliorated by ablation of the inhibitory phosphatase DUSP6. Crucially, DUSP6 ablation represents a promising engineering target to potentiate CAR T-cell efficacy in broader applications.<\/jats:p>","DOI":"10.1038\/s41392-026-02597-5","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T10:27:36Z","timestamp":1773743256000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["DUSP6 ablation restores CAR T-cell fitness impaired by tumor CD58 loss through invigoration of AP-1 signaling"],"prefix":"10.1038","volume":"11","author":[{"given":"Xinran","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9352-422X","authenticated-orcid":false,"given":"Yao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuxin","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yelei","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianshu","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhong","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1971-9889","authenticated-orcid":false,"given":"Zhiqiang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3207-3899","authenticated-orcid":false,"given":"Weidong","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"2597_CR1","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1056\/NEJMoa1709866","volume":"378","author":"SL Maude","year":"2018","unstructured":"Maude, S. 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