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Metabolic reprogramming is a hallmark of cancer, with excessive lactate accumulation driven by aerobic glycolysis profoundly reshaping the tumor microenvironment (TME). Beyond being a metabolic by-product, lactate acts as a signaling metabolite and epigenetic regulator that promotes immune suppression and therapeutic resistance. Lactate-induced acidification impairs immune cell function and reprograms macrophages, T cells, and dendritic cells toward immunosuppressive phenotypes. Moreover, lactate drives lysine lactylation of histone and non-histone proteins, linking metabolic status to transcriptional regulation and oncogenic signaling. Emerging evidence indicates that lactate and lactylation cooperatively enhance tumor survival, invasion, and resistance to chemotherapy, radiotherapy, anti-angiogenic therapy, and immunotherapy. This review summarizes mechanisms of lactate production, transport, and signaling, and discusses therapeutic strategies targeting lactate metabolism, lactylation, and TME acidification, highlighting their potential in precision and combination cancer therapy.
Li et al. (Fri,) studied this question.