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We sought to define key resistance drivers and actionable targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Integrated RNA sequencing of cabozantinib\u2010resistant RCC cells, lipid metabolomics, and PD\u2010L1 correlation analyses identified ENPP2 as a candidate driver. Its role in TKI resistance and survival signaling was validated by apoptosis, CCK\u20108, and colony formation assays in vitro and by nude\u2010mouse xenograft models in vivo. ELISA, flow cytometry and tumor cell\u2013T\u2010cell co\u2010culture assays were used to dissect ENPP2\u2010dependent CD8+ T\u2010cell dysfunction. The therapeutic benefit of pharmacologic ATX inhibition combined with standard TKI\u2013ICI regimens was tested in RCC patient\u2010derived xenograft models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The ATX\u2013LPA axis conferred TKI resistance via constitutive AKT\/mTOR activation and promoted immune evasion by upregulating PD\u2010L1 through TBK1\/IRF3 signaling, thereby impairing intratumoral CD8+ T\u2010cell function. ENPP2 enhanced PD\u2010L1 transcription by facilitating IRF3 nuclear translocation and its direct recruitment to the CD274 promoter. ATX inhibition improved the antitumor efficacy of TKI\u2013ICI therapy in preclinical models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Targeting the ATX\u2013LPA axis represents a promising strategy to overcome resistance to current TKI\u2013ICI combinations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/advs.76352","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T16:49:51Z","timestamp":1782751791000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the ATX\u2010LPA Axis Overcomes TKI Resistance and Immunosuppression in Renal Cell Carcinoma via Dual Inhibition of AKT\/mTOR and TBK1\/IRF3 Pathways"],"prefix":"10.1002","volume":"13","author":[{"given":"Jinchen","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Urology 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