Lactate and lysine lactylation: Emerging drivers shaping tumor immune evasion

Abnormal lactate metabolism and lysine lactylation (Kla) have emerged as critical factors driving tumor immune evasion through dual mechanisms of tumor metabolic reprogramming and epigenetic regulation. Tumor cells produce lactate through multiple metabolic pathways, which is then exported via monocarboxylate transporters to accumulate in the tumor microenvironment (TME). Within the TME, lactate acts as a key substrate driving the Kla of both histone and non-histone proteins. Lactate and Kla synergistically drive tumor immune evasion by acting on both tumor cells and immune cells, ultimately driving tumor initiation, proliferation, metastasis, and therapeutic resistance. Currently, therapeutic strategies targeting lactate metabolism have emerged as a research hotspot for breaking tumor immune evasion, which encompass three directions: inhibiting lactate production, blocking lactate transport, and reversing abnormal Kla. Some candidate drugs have entered clinical trials and demonstrated preliminary efficacy, yet challenges remain, including insufficient specificity, off-target toxicity, and resistance mediated by tumor metabolic plasticity. Therefore, this review systematically summarizes the mechanisms of lactate production and transport within the TME, the regulation of Kla, and their role in mediating tumor immune evasion. Anti-tumor therapeutic strategies and recent research advances targeting lactate metabolism are also clarified, which provide a theoretical basis for elucidating the metabolic mechanisms of tumor immune evasion and developing novel metabolic-immune combination therapies.