Hypoxia-inducible factors (HIFs) serve as the central signaling hub within the hypoxic tumor microenvironment, coordinating tumor proliferation, metastasis, and therapy resistance. This protein family comprises HIF-1α, HIF-2α, HIF-3α, and HIF-1β, with distinct subcellular localization patterns reflecting their isoform-specific oxygen-sensing mechanisms. Tumor-associated HIF expression is regulated through a multifaceted network involving non-coding RNAs (ncRNAs), mitochondrial metabolites, and post-translational modifications (PTMs). These aberrantly expressed HIFs then orchestrate biologically important processes including metabolic reprogramming, angiogenesis, and pro-tumorigenic inflammation. It is important to note that current evidence regarding HIF-3α function remains limited and requires further validation in vivo. This review first systematically deciphers the mechanisms governing HIF dysregulation in tumors, before elucidating the key biological processes involved. We then synthesize advances in HIF-targeting inhibitors. These pivotal findings provide a solid theoretical foundation and novel insights for both anticancer therapies targeting this critical “molecular switch” and translational research focusing on HIFs as promising therapeutic targets.

Hypoxia-inducible factors  /  Hypoxic tumor microenvironment  /  Regulation mechanism  /  Immune regulation  /  Therapy resistance  /  HIF-Targeting inhibitors  /  Therapeutic targets  /  Tumor treatment