Fig. 3: The value of lactate in the radiotherapy-mediated TME.
From: Radiotherapy remodels the tumor microenvironment for enhancing immunotherapeutic sensitivity
RT upregulates the expression of PKM2 and LDHA in tumor cells, which catalyze glycolysis to produce lactate. Irradiation causes a significant increase in HIF-1α activity and regulates LDHA activity. PKM2 has been reported to stabilize HIF-1α. Lactate is transported into TME via MCT. Lactate accumulation inhibits NFAT in T and NK cells, thereby reducing IFN-γ synthesis. Lactate binds to GPR81 on MDSCs to activate Akt. Subsequently, functional genes S100A8/9, Arg1 and MMPs are upregulated through the mTOR/HIF-1α/STAT3 pathway, suggesting activation of MDSCs. Tregs take up lactate in TME via MCT1, which promotes NFAT1 entry into the nucleus and induces PD-1 expression. In addition, RT causes a decrease in LDHA expression and inhibits the conversion of pyruvate to lactate in microglia. Solid lines represent anti-tumor effects and dashed lines represent pro-tumor effects.
