Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

Abstract

Inadequate oxygen supply, or hypoxia, is characteristic of the tumor microenvironment and correlates with poor prognosis and therapeutic resistance. Hypoxia leads to the activation of the hypoxia-inducible factor (HIF) signaling pathway and stabilization of the HIF-α subunit, driving tumor progression. The homologous alpha subunits, HIF-1α and HIF-2α, are responsible for mediating the transcription of a multitude of critical proteins that control proliferation, angiogenic signaling, metastasis, and other oncogenic factors, both differentially and sequentially regulating the hypoxic response. Post-translational modifications of HIF play a central role in its behavior as a mediator of transcription, as well as the temporal transition from HIF-1α to HIF-2α that occurs in response to chronic hypoxia. While it is evident that HIF-α is highly dynamic, HIF-2α remains vastly under-considered. HIF-2α can intensify the behaviors of the most aggressive tumors by adapting the cell to oxidative stress, thereby promoting metastasis, tissue remodeling, angiogenesis, and upregulating cancer stem cell factors. The structure, function, hypoxic response, spatiotemporal dynamics, and roles in the progression and persistence of cancer of this HIF-2α molecule and its EPAS1 gene are highlighted in this review, alongside a discussion of current therapeutics and future directions.

HIF-2α regulates proliferation, invasion, and metastasis of hepatocellular carcinoma cells via VEGF/Notch1 signaling axis after insufficient radiofrequency ablation

“…Hypoxia, the insufficient supply of oxygen to tissues, is an inherent characteristic of the tumor microenvironment and exists in almost all solid tumor sites (50). Tumor hypoxia leads to the activation of the HIF signaling pathway, and HIF is involved in mediating many important processes, such as tumor growth, metastasis, metabolism, and angiogenesis (51). HIF is a heterodimer complex consisting of a HIF-a subunit degraded by an oxygen-dependent proteasome and a constitutively expressed HIF-b subunit (52).…”

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

“…Collectively, HIF-2α plays an important role in immunosuppression mainly through controlling TAM-mediated immunosuppression in hypoxic TME. Small-molecule HIF-2α inhibitors such as PT2399, PT2977 and 32-1340 have been shown to poses significant anti-tumor properties and enhance the efficacy of immune checkpoint inhibitors [43,68,69]. Clearly, further investigations are warranted for better understanding of the role of HIF-2α in tumor immune responses.…”

The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies

“…Most preclinical studies collect and process tumor tissues in normoxia rather than physioxia, which contributes to therapy failure in clinic despite promising preclinical results [ 7 ]. Hypoxia contributes to various critical aspects of cancer, including genome instability [ 8 ], autophagy [ 9 ], metabolic reprogramming [ 10 , 11 ], angiogenesis [ 12 ], migration, invasion [ 13 ], extracellular matrix remodeling [ 14 ], epithelial mesenchymal transition (EMT) [ 15 ], stem cell maintenance [ 16 ], immune evasion [ 17 ] and therapy resistance [ 18 ] (Fig. 1 ).…”