Fig. 1.

Approved VEGF-targeted and mTOR-targeted antiangiogenic drugs and their specific targets with their mode of action. Increased tumor hypoxia during antiangiogenic therapy is the key player for developing TKI resistance, with an accumulation of HIF-alpha. Consequently, different alternative HIF and/or non HIF-derived proangiogenic (e. g. ephrin, angiopoietin, FGF, VEGF, PIGF) and c‑MET (cell motility, proliferation, differentiation, migration and invasion) signaling pathways are activated, being responsible for further tumor progression. Moreover, hypoxia leads to an activation of bone marrow-derived cells consisting of circulating endothelial progenitor cell (CEP), forming new blood vessels in the tumor (vasculogenesis). Under hypoxia, PD-L1 upregulation was dependent on HIF-2a in RCC, being associated with simultaneous VEGF overexpression. CEP circulating endothelial progenitor, FGF (R) fibroblast growth factor (receptor), PDGF (R) platelet-derived growth factor (receptor), PIGF placental growth factor, VEGF (R) vascular endothelial growth factor (receptor)