Research Progress on Lactate-Mediated Tumor Metabolic Microenvironment-Driven Immunotherapy and Metabolic Reprogramming Strategies

Abstract

Abnormal metabolites (such as lactate) in the tumor metabolic microenvironment (TME) significantly affect the efficacy of immunotherapy by reshaping the function of immune cells. However, the mechanism of lactate-mediated immunosuppression has not been fully elucidated, and the clinical translation of targeted metabolic intervention strategies faces challenges of drug resistance and toxicity. This study systematically reviewed the bidirectional regulatory mechanism of lactate on CD8+ T cells and regulatory T cells (Treg), integrated the TCGA/GEO database to analyze the association between metabolic enzyme gene expression and prognosis, and compared the preclinical and clinical trial data of targeted lactate metabolism. The results showed that: (1) lactate inhibited T cell glycolytic activity by acidifying the microenvironment, while activating the HIF-1α/GPR81 signaling axis to promote Treg differentiation; (2) LDHA inhibitors (such as GSK2837808A) and MCT1/4 blockers can reduce TME lactate levels and enhance the efficacy of PD-1 antibodies; (3) Clinical translation needs to address the problems of metabolic targeted drug delivery efficiency and the lack of patient stratification markers. In summary, targeting lactate metabolism is a key breakthrough in reversing resistance to immunotherapy, and its efficacy depends on precise intervention guided by multi-omics. This article suggests that dynamic lactate monitoring technology and nano-drug delivery systems should be developed in the future, and metabolic-immune dual-target combined treatment plans should be designed to optimize clinical outcomes.