Targeting SLC16A3 reverses lactate-driven immune dysfunction and immunotherapy resistance in ccRCC

Metabolic reprogramming and immune evasion are characteristics of clear cell renal cell carcinoma (ccRCC), but the intrinsic mechanisms of tumor cells in these processes have not been fully determined. Here, through an integrated analysis of 120 publicly available scRNA-seq datasets, spatial transcriptomics, and multiple independent clinical cohorts, we identify SLC16A3 as a major determinant of highly malignant tumor cell status in ccRCC. SLC16A3high cells exhibit enhanced glycolytic activity, increased invasiveness, and strong association with adverse patient outcomes. Mechanistically, SLC16A3-driven glycolysis triggers intracellular and extracellular lactate accumulation, which in turn induces H4K12 lactylation (H4K12la), activates NF-κB, and sustains IL8 expression. This metabolic–epigenetic–cytokine cascade directly impairs CD8⁺ T-cell function, promotes exhaustion, and establishes an immunosuppressive microenvironment. Using molecular docking, biophysical binding assays, tumor organoid–T cell cocultures, orthotopic ccRCC models, and humanized mice, we identify amuvatinib as a potent SLC16A3-targeting small-molecule inhibitor that suppresses tumor progression and restores sensitivity to αPD-1 therapy. Our findings reveal a previously unrecognized mechanism by which SLC16A3 coordinates metabolic and immune reprogramming to drive ccRCC progression and immunotherapy resistance, and highlight SLC16A3 inhibition as a promising therapeutic strategy for metastatic or immune-refractory ccRCC.