Fig. 5
From: Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions
Hypoxia remodels CTL immune effect. HIF-1α in CTL is upgraded by TCR-PKC and Ca2+/calcineurin, PI3K/mTOR, NF-κB, NF-κB, JAK-STAT3, MAPK pathway. Deletion of pVHL impaired HIF-1α degradation. HIF-1α and HIF-1β dimerization stimulates downstream factor expression, such as perforin, IFN-γ, TNF-α, which can enhance the antitumor efficacy of CTL. However, some experiments elaborate the opposite results. Hypoxia inhibits the expression of IFN-γ, TNF-α, granzyme B, IL-2, perforin and NKG2D, while promoting PD-L1,PD-1 and CTLA-4 expression. CTL increases glucose uptake via GLUT1, which is metabolized to lactate by glycolytic enzymes PK and LDH. Lactate acidifies the TME, which inhibits CTL activation
