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

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.