Table 1 Summary of Hypoxia-targeting agents with potential to improve immunotherapy

Evofosfamide (TH-302)

Hypoxia activated prodrug

Upon activation in oxygen deficient regions, evofosfamide is converted selectively to the drug’s active form, dibromo isophosphoramide mustard, a potent alkylator

[87]

Praziquantel (EO9)

Hypoxia activated prodrug

Apaziquone can be converted to a cytotoxic species after enzymatic activation

[88]

SN30000

Hypoxia activated prodrug

Improved tirapazamine analogue with potential for targeting tumor hypoxia in humans

[27]

Doxorubicin

Targeting HIF DNA binding

Inhibits binding of HIF-1 to the HRE sequence

[12]

Daunorubicin

Targeting HIF DNA binding

Inhibits binding of HIF-1 to the HRE sequence

[12]

Anti-sense HIF-1a therapy

Anti-sense HIF-1a

Engineered down-regulation of HIF-1a by gene transfer of an antisense HIF-1a plasmid leads to the down-regulation of VEGF, and decreased tumor microvessel density.

[89]

PX-478

HIF-1α inhibitor

Reduces expression of Foxp3 and VEGF transcript and/or protein, molecules that are directly controlled by HIF-1

[90]

CRLX101

HIF-1α inhibitor

Suppresses HIF-1α as well as topoisomerase 1

[91]

POM-1

ENTPD2 inhibitor

Depletes MDSCs and mitigates cancer growth

[52]

anti-CAIX antibodies

Targeting CA IX

Mediates immune killing of CAIX+ tumor cells

[92]

SLC-0111

CA IX inhibitor

Decreases glycolytic metabolism of tumor cells and acidification of the TME

[93]

SCH58261

A2AR antagonist

Inhibits immunosuppressive adenosine

[94]

Oxygen therapy

Supplementing oxygen

Decreases the tumor hypoxia and HIF-1α-CD39/CD73-driven extracellular adenosine accumulation

[95]

Metformin

Inhibiting oxygen consumption

Inhibits both oxygen consumption and subsequent tumor hypoxia

[96]

Bevacizumab

Inhibiting the binding of VEGF to its receptors

Anti-angiogenesis

[97]

Lenvatinib

Multi-kinase VEGFR inhibitor

Anti-angiogenesis

[98]

Cabozantinib

Tyrosine-kinase inhibitor

Anti-angiogenesis

[38]