Fig. 4

Combination therapy with immunotherapy or metabolic therapy. Combining blockage of HIF-1α or HIF-2α with immunotherapy (left). PD-1/PD-L1/CTLA-4, the immune checkpoint proteins on T cells which often transmit “immune switch off” signal, is correlated with HIF pathway, and tumor hypoxic status usually leads to the failure of immunotherapy. Therefore, by combining HIF/hypoxia inhibitors with PD-1/PD-L1/CTLA-4 inhibitors, it has been proved to significantly raise T cell immune activity, reducing the amount and malignant potential of tumors. • Immunotherapies: PD-1 inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor. • HIF-1 pathway inhibitors: POG, X4-136, POM-1, ARL67156, Ganetespib. • HIF-2 pathway inhibitors: PT2385, PT2399. Combining blockage of HIF-1α or HIF-2α with metabolic therapy (right). Pyruvate flux through TCA cycle is downregulated in cancer cells. Glycolysis sustains the high proliferative rate of cancer cells. Targeting of HIF-1α may be a prerequisite for cancer metabolism targeted therapy. • Metabolic therapies: D-allose, dichloroacetate and vitamin C. • HIF-1 pathway inhibitors: polydatin, LY294002 and BAY872243. • Metabolic and HIF-1 pathway inhibitors: 2-DG, cardamonin and metformin. Abbreviation: IGF-1 = Insulin like growth factor-1; PI3K = Phosphoinositide-3-kinase; Akt = protein kinase B; mTOR = mechanistic target of rapamycin; mTORC2 = Mammalian Target of Rapamycin Complex 2; HIF = hypoxia inducible factor; HRE = Hypoxia-response element; PHD2 = prolyl hydroxylase domain protein 2; PP2A = Protein phosphatase 2A; HSP90 = Heat shock protein 90; CXCR4 = chemokine receptor type 4; COX2 = Cyclooxygenase-2; PGE2 = prostaglandin E2; MAPK = mitogen-activated protein kinase; ENTPD2 = Ectonucleoside Triphosphate Diphosphohydrolase 2; MDSC = Myeloid Derived Suppressor Cell; PD-1 = Programmed death-1; PD-L1 = Programmed death-ligand 1; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; CD80/86 = Cluster of differentiation 80/86; APC = Antigen-presenting cell; LDHA = Lactate dehydrogenase A; TCA = tricarboxylic acid