Abstract
Non-small cell lung cancer (NSCLC) is characterized by high incidence and mortality, with a low five-year survival rate. Lactate metabolism plays a central role in the metabolic reprogramming of NSCLC. Beyond serving as the end-product of glycolysis, lactate accumulates in the tumor microenvironment (TME), contributing to acidification, and can also enter the tricarboxylic acid cycle to participate in energy metabolism. Moreover, the G protein-coupled receptor 81 (GPR81)/phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling axis induces the expression of immune checkpoint molecules, such as programmed death-ligand 1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), thereby suppressing the functions of T lymphocytes and natural killer cells and establishing an immunosuppressive microenvironment. Lactate further promotes epithelial-mesenchymal transition and tumor metastasis, and drives NSCLC chemoresistance and relapse via histone lactylation. Clinical studies indicate that enhanced lactate metabolism is associated with NSCLC progression and chemotherapy resistance, while targeting lactate metabolism in combination with immunotherapy exerts synergistic antitumor effects. Therefore, comprehensive inhibition of lactate metabolism together with enhancement of antitumor immunity may improve the efficacy of precision therapy in NSCLC.
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