Revisiting the HIF switch in the tumor and its immune microenvironment

Hypoxia-inducible factor (HIF)-1α and HIF-2α play nonoverlapping, complementary roles in solid tumors by promoting changes in metabolism, enhancing angiogenesis, and inducing a more aggressive phenotype. The HIFs also modulate gene expression profiles of the non-malignant immune cell types within the tumor microenvironment (TME), sculpting a tumor-permissive niche that facilitates tumor progression and drives resistance to therapy. HIF inhibition may impact tumor progression by directly blocking its tumor-promoting function in tumor cells and by modulating the tumor-enabling function of the immune TME, with potential for improving responses to immune checkpoint blockade (ICB). Selective HIF-2α inhibition provides clinical benefit for the treatment of clear cell renal cell carcinoma (ccRCC) and is currently being evaluated in other solid tumor types. Due to their complementarity, the direct targeting of both HIF-1α and HIF-2α may provide additional benefit over that of targeting each isoform alone. Hypoxia is a hallmark of all solid tumors and their metastases. This leads to activation 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 response. The best characterized HIF isoforms, HIF-1α and HIF-2α, show nonoverlapping and often antagonistic roles. With the recent availability of inhibitors that target one or both HIFs, including the first-in-class selective HIF-2α inhibitor belzutifan, the prospect of HIF-α isoform-selective targeting is now a reality. Here, we summarize current knowledge on the unique contributions of the two HIF-α isoforms to tumor progression in the context of the complex tumor immune microenvironment, highlighting important considerations for therapy. Hypoxia is a hallmark of all solid tumors and their metastases. This leads to activation 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 response. The best characterized HIF isoforms, HIF-1α and HIF-2α, show nonoverlapping and often antagonistic roles. With the recent availability of inhibitors that target one or both HIFs, including the first-in-class selective HIF-2α inhibitor belzutifan, the prospect of HIF-α isoform-selective targeting is now a reality. Here, we summarize current knowledge on the unique contributions of the two HIF-α isoforms to tumor progression in the context of the complex tumor immune microenvironment, highlighting important considerations for therapy. (a disintegrin and metalloproteinase domain–containing protein 10 ) a cell surface protein that cleaves membrane proteins. cancer-associated fibroblasts are a fibroblast-related cell type found in the tumor microenvironment. clear cell renal cell carcinoma is the most common type of kidney cancer. binds to HIF to enhance transcription activation. a protein that downregulates immune responses. an enzyme that hydrolyzes 5′-triphosphates. cells that make up blood vessels. an asparaginyl hydroxylase that regulates HIF. primary liver cancer. enzymes that remove acetyl groups from histone proteins. transcription factors activated by hypoxia. a core sequence of 5′-RCGTG-3′ bound by HIF. half-maximal inhibitory concentration is the amount of a drug needed to inhibit a biological process by half. a type of immunotherapy that blocks immune checkpoints in cytotoxic T cells, resulting in reactivation of T cells. a protein that acts as a ‘kill me’ signal. a sensor of cell stress expressed on NK cells. the percentage of people within a study who are still alive after a specified time. a cancer model where tissue or cancer cells are taken from a patient and implanted into a mouse. a protein found on the surface of immune cells that modulates T cell activity. the cell surface ligand that binds PD-1. the length of time that a person lives with a disease that does not get worse. enzymes that hydroxylate HIF. a transcriptomic methodology that examines gene expression in single cells. macrophages that are found within the tumor microenvironment. the environment around a tumor including non-neoplastic cells. a drug that inhibits tyrosine kinases. a protein that ubiquitinates hydroxylated HIF-α.