Lactate Metabolic Reprogramming Reverses CD8⁺ T Cell Exhaustion: A New Target for Cancer Immunotherapy

Lactate accumulation in the tumor microenvironment is an important factor inducing CD8⁺ T cell exhaustion and immunotherapy resistance, but whether reprogramming lactate metabolism can reverse CD8⁺ T cell exhaustion remains unclear. This study aims to explore the effects of targeted lactate metabolism on CD8⁺ T cell function and anti-tumor immunotherapy. Single-cell RNA sequencing, metabolomics, flow cytometry, and immunohistochemistry were used to analyze the lactate metabolism characteristics and exhaustion phenotypes of tumor-infiltrated CD8⁺ T cells; Genetics or pharmacological methods were used to regulate lactate dehydrogenase A (LDHA) and the lactate transporter MCT1/4, and to evaluate anti-tumor effects and synergistic effects with anti-PD-1 therapy in tumor-bearing mouse models of B16-OVA and MC38. Lactate uptake in tumor-infiltrating CD8⁺ T cells increases, with significant upregulation of MCT1/4 and LDHA, accompanied by decreased mitochondrial membrane potential, impaired oxidative phosphorylation, and increased expression of depletion markers such as PD-1, TIM-3, LAG-3, and TOX/NR4A. Inhibiting LDHA or blocking MCT1/4 lowers intracellular lactate levels, restores mitochondrial function and oxidative phosphorylation, enhances secretion of IFN-γ, TNF-α, and granzyme B, and downregulates depletion-related transcriptional programs. In tumor-bearing mice, reprogramming of lactate metabolism significantly inhibits tumor growth, increases the proportion of tumor-infiltrating CD8⁺ T cells and effector memory phenotypes, and produces synergistic effects with anti-PD-1 therapy. Mechanistically, lactate regulates the expression of exhaustion-related genes through histone lactation modification, while metabolic intervention can reverse this epigenetic program. Targeted lactate metabolism reprogramming can effectively reverse CD8⁺ T cell exhaustion, enhance the efficacy of tumor immunotherapy, and provide new potential targets for solid tumor immunotherapy.