Revisiting the HIF switch in the tumor and its immune microenvironment

Hypoxia is a hallmark of all solid tumors and their metastases. This leads to acti-vation of the hypoxia-inducible factor (HIF) family of transcription factors, which modulate gene expression within both tumor cells and immune cells within the tumor microenvironment, influencing tumor progression and treatment re-sponse. The best characterized HIF isoforms, HIF-1 alpha and HIF-2 alpha, show nonover -lapping and often antagonistic roles. With the recent availability of inhibitors that target one or both HIFs, including the first-in-class selective HIF-2 alpha inhibitor belzutifan, the prospect of HIF-alpha isoform-selective targeting is now a reality. Here, we summarize current knowledge on the unique contributions of the two HIF-alpha isoforms to tumor progression in the context of the complex tumor immune microenvironment, highlighting important considerations for therapy.