Lactate as a Master Regulator of Immune Suppression: From Metabolic Waste to Epigenetic Checkpoint in Colorectal Cancer

Abstract

Colorectal cancer, especially the microsatellite-stable subtype, which accounts for 85% to 95% of cases, resists immune checkpoint inhibitors largely due to metabolic reprogramming in the tumor microenvironment. Lactate has evolved from a waste product into a central immunosuppressive regulator. Oncogenic KRAS and BRAF mutations drive aerobic glycolysis, causing glucose deprivation and massive lactate accumulation in the tumor microenvironment. Lactate suppresses immunity through three parallel mechanisms. It signals via GPR81 to recruit polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and inhibit T-cell function. It contributes to histone H3K18 lactylation, which silences effector genes including IFN-γ and GZMB while upregulating PD-L1 expression. It also acidifies the microenvironment to pH 6.0–6.5, directly impairing NK and T-cell activity. Concurrent lipid abundance stabilizes the MCT4 lactate exporter, forming a bidirectional feed-forward loop that amplifies lactate effects. Spatial metabolic heterogeneity creates distinct immune battlefields, with a supportive ‘metabolic oasis’—a concept proposed in this review—at the invasive front and a deeply immunosuppressive core. Thus, lactate acts as an epigenetic and signaling hub that bridges oncogenic mutations, metabolic competition and immune evasion. Targeting lactate metabolism through LDHA or MCT4 inhibition, modulation of histone lactylation, or disruption of lactate-lipid crosstalk, when combined with classical immune checkpoint blockade and guided by spatial biomarkers, offers a promising strategy to overcome immunotherapy resistance in this challenging subtype.