Fig. 3

HIF1A regulates tumor immune escape under hypoxic conditions. Under normoxic conditions, HIF1A is hydrolyzed by prolyl-4-hydroxylase (PHD). Von Hippel-Lindau (VHL) then recognizes and binds to HIF1A, leading to rapid proteasomal degradation of HIF1A, rendering tumor cells susceptible to immune surveillance. Under hypoxic conditions, HIF1A is protected from degradation and translocates to the nucleus, where it dimerizes with hydrocarbon receptor nuclear translocator (ARNT) to form HIF1 and binds to target gene hypoxic response elements (HREs). HIF1 induces cytotoxic T lymphocyte (CTL) apoptosis by upregulating PD-L1 expression, which enhances tumor cell resistance to lysis. Moreover, HIF1A causes MIC shedding by impairing NO signaling, allowing escape from NK cell immune surveillance. The HIF1-GAL3ST1-sulfatide signaling axis promotes immune escape by increasing tumor cell-platelet binding. HIF1 also regulates CD47 expression to promote escape from phagocytosis and promotes tumor angiogenesis through upregulation of vascular endothelial growth factor (VEGF), which facilitates immune escape by enabling metastasis