HIF-1α Inhibition Improves Anti-Tumor Immunity and Promotes the Efficacy of Stereotactic Ablative Radiotherapy (SABR)

Chang W. Song, Hyunkyung Kim, Haeun Cho, Mi Sook Kim, Sun Ha Paek, Heon Joo Park, Robert J. Griffin, Stephanie Terezakis, Lawrence Chinsoo Cho

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


High-dose hypofractionated radiation such as SABR (stereotactic ablative radiotherapy) evokes an anti-tumor immune response by promoting a series of immune-stimulating processes, including the release of tumor-specific antigens from damaged tumor cells and the final effector phase of immune-mediated lysis of target tumor cells. High-dose hypofractionated radiation also causes vascular damage in tumors, thereby increasing tumor hypoxia and upregulation of hypoxia-inducible factors HIF-1α and HIF-2α, the master transcription factors for the cellular response to hypoxia. HIF-1α and HIF-2α are critical factors in the upregulation of immune suppression and are the master regulators of immune evasion of tumors. Consequently, SABR-induced increase in anti-tumor immunity is counterbalanced by the increase in immune suppression mediated by HIFα. Inhibition of HIF-1α with small molecules such as metformin downregulates immunosuppressive pathways, including the expression of immune checkpoints, and it improves or restores the anti-tumor immunity stimulated by irradiation. Combinations of HIFα inhibitors, particularly HIF-1α inhibitors, with immune checkpoint blocking antibodies may represent a novel approach to boost the overall anti-tumor immune profile in patients and thus enhance outcomes after SABR.

Original languageEnglish (US)
Article number3273
Issue number13
StatePublished - Jul 1 2022

Bibliographical note

Funding Information:
Funding: University of Minnesota Cancer Center Internal Research fund to C.W.S. and NRF-2020R1A2C2101772 to H.J.P., Winthrop P. Rockefeller Cancer Institute Teams Science Award (R.J.G.)

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.


  • HIF-1α
  • HIF-1α inhibitor
  • HIF-2α
  • HIF-2α inhibitor
  • SABR
  • immune checkpoints
  • immunotherapy
  • tumor hypoxia


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