SLC16A3-Induced Lactate Remodeling Drives Immune Evasion in Clear Cell Renal Cell Carcinoma via an Autocrine GPR81-ERK-c-MYC Feedback Loop

Background: ; monocarboxylate transporter 4, MCT4) rewires tumor lactate metabolism to promote immune escape in ccRCC is still lacking. Aims: -mediated lactate reprogramming in regulating glycolysis and immune suppression, and validate the therapeutic potential of MCT4 inhibition combined with anti-programmed cell death protein-1 (anti-PD-1) therapy for ccRCC. Study Design: Integrated in vivo CRISPR screening, functional assays, and clinical validation. Methods: -overexpressing 786-O and SN12C ccRCC cells were established. RNA sequencing, protein stability, ubiquitination, and phosphorylation analyses were conducted to elucidate the underlying molecular mechanisms. Results: T-cell function. Concurrently, exported lactate engaged tumor GPR81 to activate autocrine ERK signaling and phosphorylate c-MYC at Ser62, preventing F-box and WD repeat domain-containing 7-mediated degradation. This stabilized c-MYC upregulated lactate dehydrogenase A, glucose transporter 1, and hypoxia-inducible factor 1 alpha, forming a self-sustaining glycolytic feedback loop uniquely amplified in the von Hippel-Lindau-deficient background of ccRCC. Clinically, tissue microarray analysis indicated a trend toward worse progression-free survival in patients with high MCT4 expression. Furthermore, combining the MCT4 inhibitor MSC-4381 with PD-1 blockade markedly reduced tumor volume in immunocompetent mice, demonstrating enhanced combinatorial efficacy. Conclusion: -induced lactate reprogramming drives immune resistance in ccRCC via two converging mechanisms: extracellular lactate-mediated immunosuppression through M2 macrophage polarization and an autocrine GPR81-ERK-c-MYC glycolytic feedback loop. These findings highlight MCT4 blockade combined with immune checkpoint inhibition as a rational strategy to overcome immunotherapy resistance.