SLC6A3 Dopaminergic Signaling Subverts Spliceosomal Fidelity to Promote Immune Checkpoint Inhibitor Resistance in Clear Cell Renal Cell Carcinoma [1]

Clear cell renal cell carcinoma (ccRCC) remains refractory to immune checkpoint inhibitors (ICIs) despite its high tumor mutational burden, highlighting an urgent need to elucidate tumor-intrinsic mechanisms of immune escape. Here, leveraging lineage tracing and single-cell multi-omic profiling in immunocompetent models, we identify a pre-existing SLC6A3-positive tumor subpopulation that persists following anti-PD-1 therapy and orchestrates immune evasion by exploiting renal dopamine uptake. SLC6A3 overexpression is robustly associated with diminished infiltration of cytotoxic CD8⁺ T cells and myeloid dendritic cells, establishing it as a biomarker of ICI resistance in ccRCC. Mechanistically, SLC6A3-mediated dopamine import disrupts the MHC-I antigen presentation pathway through direct sequestration of the spliceosomal regulator USP39, resulting in aberrant splicing of B2m and Tap1/2 pre-mRNAs and consequent loss of antigenicity. This disconnects high mutational burden from effective immune surveillance, enabling sustained immune escape. Critically, both genetic and pharmacologic inhibition of SLC6A3 restore antigen presentation competency, potentiate CD8⁺ T cell cytotoxicity, and synergize with anti-PD-1 treatment to achieve durable tumor regression in vivo. Our findings redefine dopamine as a tumor-intrinsic immunosuppressant in ccRCC and nominate the SLC6A3-USP39 axis as a tractable target for reversing antigen presentation defects and overcoming microenvironment-driven ICI resistance.