Targeting the ATX‐LPA Axis Overcomes TKI Resistance and Immunosuppression in Renal Cell Carcinoma via Dual Inhibition of AKT/mTOR and TBK1/IRF3 Pathways

ABSTRACT Background Therapeutic resistance limits durable survival in advanced/metastatic renal cell carcinoma (RCC) treated with first‐line tyrosine kinase inhibitor (TKI) plus immune checkpoint inhibitor (ICI). We sought to define key resistance drivers and actionable targets. Methods Integrated RNA sequencing of cabozantinib‐resistant RCC cells, lipid metabolomics, and PD‐L1 correlation analyses identified ENPP2 as a candidate driver. Its role in TKI resistance and survival signaling was validated by apoptosis, CCK‐8, and colony formation assays in vitro and by nude‐mouse xenograft models in vivo. ELISA, flow cytometry and tumor cell–T‐cell co‐culture assays were used to dissect ENPP2‐dependent CD8+ T‐cell dysfunction. The therapeutic benefit of pharmacologic ATX inhibition combined with standard TKI–ICI regimens was tested in RCC patient‐derived xenograft models. Results The ATX–LPA axis conferred TKI resistance via constitutive AKT/mTOR activation and promoted immune evasion by upregulating PD‐L1 through TBK1/IRF3 signaling, thereby impairing intratumoral CD8+ T‐cell function. ENPP2 enhanced PD‐L1 transcription by facilitating IRF3 nuclear translocation and its direct recruitment to the CD274 promoter. ATX inhibition improved the antitumor efficacy of TKI–ICI therapy in preclinical models. Conclusions Targeting the ATX–LPA axis represents a promising strategy to overcome resistance to current TKI–ICI combinations.