Lactate-rich tumor microenvironment (Lactate-rich TME)

The lactate-rich tumor microenvironment is a physiological state characterized by the accumulation of lactic acid and a concomitant decrease in extracellular pH within solid tumors. This phenomenon is primarily driven by the Warburg effect, where cancer cells exhibit high rates of glycolysis and convert glucose to lactate even under normoxic conditions (San-Millán & Brooks, 2017). Lactate acts not only as a metabolic byproduct but also as a potent signaling molecule, or oncometabolite, that facilitates tumor growth, angiogenesis, and tissue remodeling (Ferguson et al., 2018). Crucially, high lactate levels create an immunosuppressive milieu by inhibiting the effector functions of T cells and natural killer cells while promoting the activity of regulatory T cells and myeloid-derived suppressor cells (Brand et al., 2016). Therapeutic interventions targeting this environment focus on inhibiting lactate production via lactate dehydrogenase (LDH) or blocking its transport through monocarboxylate transporters (MCTs) to restore immune surveillance and enhance the efficacy of chemotherapy and immunotherapy (Doherty & Cleveland, 2013). By disrupting these metabolic pathways, researchers aim to normalize the tumor microenvironment and overcome resistance to standard-of-care treatments.

Other names

Acidic tumor microenvironmentLactate-dense TMEWarburg-driven microenvironmentLactic acid-rich TME

Inhibition of monocarboxylate transporters (MCT1 and MCT4) to block lactate efflux and influx, inhibition of lactate dehydrogenase A (LDHA) to prevent the conversion of pyruvate to lactate, and antagonism of the G protein-coupled receptor 81 (GPR81) to disrupt lactate-mediated signaling pathways (Doherty & Cleveland, 2013; Ferguson et al., 2018).