Abstract: Tumor cells preferentially engage in aerobic glycolysis (the Warburg effect) despite normoxic conditions, manifesting in pathological glucose avidity and excessive lactate accu-mulation relative to adjacent normal tissues. Beyond serving as a glycolytic endpoint, lactate acts as a versatile oncometabolite. It epigenetically reinforces multidrug resistance by remod-eling the extracellular microenvironment and driving transcriptional reprogramming via intra-cellular lactylation. Mechanistic studies reveal that lactate-mediated chemoresistance arises from stabilization of DNA repair machineries and metabolic adaptation pathways. This review synthesizes current understanding of lactate/lactylation-mediated therapeutic resistance mech-anisms across solid tumors, while proposing actionable targets within lactate metabolic cir-cuitry. Pharmacological disruption of lactate homeostasis coupled with lactylation modulation may reverse tumor adaptive resilience and resensitize refractory cancers to conventional ther-apeutics.
Xing et al. (Thu,) studied this question.