Lactate metabolism in the metastatic cascade: Microenvironmental remodeling, epigenetic reprogramming, and...

Once considered a metabolic byproduct of the Warburg effect, lactate functions as a dynamic signaling effector and a central driver of the metastatic cascade. This comprehensive review elucidates how tumor-derived lactate systematically remodels the tumor microenvironment (TME) to facilitate distant dissemination. Spatial compartmentalization via monocarboxylate transporters (MCT1 and MCT4) establishes a reciprocal metabolic shuttle that sustains the bioenergetic demands of invasive neoplastic subpopulations. Continuous lactate and proton co-extrusion drive extracellular acidification, which dismantles structural tissue boundaries via matrix metalloproteinases (MMPs) and initiates the epithelial-mesenchymal transition (EMT) through HCAR1 signaling. Intracellular lactate functions as a direct epigenetic modulator. It fuels p300-mediated histone lactylation to sustain mesenchymal and stemness gene expression, and non-histone lactylation of the cGAS-STING pathway suppresses type I interferon production, enabling immune evasion during intravascular transit. Lactate suppresses local immunosurveillance by exhausting cytotoxic CD8⁺ T lymphocytes and promoting the activity of immunosuppressive regulatory T cells (Tregs) and M2-polarized macrophages. Targeting lactate metabolism offers therapeutic potential; isolated small-molecule inhibitors of LDHA and MCTs face pharmacological hurdles, including adaptive homeostatic resistance and off-target toxicity. This review highlights the multi-targeted network pharmacology of Traditional Chinese Medicine formulations. Synergistic pairing of these systemic metabolic interventions with modern immune checkpoint blockade offers an integrated therapeutic framework to neutralize the metastatic niche and prevent disease relapse.