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

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.