GGPS1 augments CD8+ T cell antitumor by activating glycolysis in clear cell renal cell carcinoma

CD8 + T lymphocytes are critical for rejecting cancer cells but often lose functionality in the immunosuppressive tumor microenvironment. Understanding this process could improve cancer immunotherapy. The enzyme GGPS1, which produces geranylgeranyl pyrophosphate (GGPP), has an unclear impact on CD8 + T cell cytotoxic function and tumor immune escape in clear cell renal cell carcinoma (ccRCC). To investigate how GGPS1 deficiency in T cells affects tumor progression, we established Renca tumor models in mice with T-cell-specific deletion of GGPS1. A combination of approaches—including real-time PCR, western blotting, flow cytometry, in vitro cytotoxicity assays, Seahorse metabolic analysis, and measurements of glucose uptake and lactic acid secretion—was employed to dissect the role of GGPS1 in CD8⁺ T cell cytotoxicity and glycolysis. In parallel, adoptive transfer studies were conducted to evaluate the antitumor potential of CD8⁺ T cells engineered to overexpress GGPS1. CD8⁺ T cells isolated from ccRCC patients who failed to respond to PD-1 blockade exhibited markedly lower GGPS1 expression. In mice, T-cell-specific deletion of GGPS1 accelerated tumor growth, accompanied by diminished infiltration of cytotoxic CD8⁺ T cells and elevated expression of exhaustion markers—including PD-1, TIM-3, LAG-3, and TOX—on tumor-infiltrating CD8⁺ T cells. Silencing GGPS1 impaired cytokine production and antitumor activity, whereas restoring GGPS1 expression reinforced both functions. Notably, exogenous GGPP fully rescued the defects in cytotoxicity and glycolysis induced by GGPS1 knockdown. Mechanistically, GGPS1 promoted MEK/ERK signaling, and the MEK inhibitor trametinib abolished GGPP-driven enhancement of CD8⁺ T cell cytotoxicity and glycolysis. Finally, elevating GGPS1 levels in CD8⁺ T cells boosted the efficacy of both adoptive immunotherapy and immune checkpoint blockade in ccRCC models. These findings highlight the essential function of GGPS1 in regulating glycolysis and cytotoxicity in CD8 + T cells, offering potential therapeutic strategies for clinical tumor immunotherapy in ccRCC.