Hypoxia-Inducible Factor Prolyl Hydroxylase (HIF-PHD) Inhibitors: A Therapeutic Double-Edged Sword in Immunity and Inflammation

Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors, clinically established for treating renal anemia, are emerging as potent immunomodulators with therapeutic potential far beyond erythropoiesis. This review dissects the mechanistic basis of their action, centered on the stabilization of hypoxia-inducible factor-alpha (HIF-α), a master transcription factor that orchestrates fundamental shifts in immune cell function. We synthesize evidence showing how HIF-α stabilization alters innate immunity, recalibrates T- and B-cell responses, and reshapes inflammatory signaling. This activity translates to significant efficacy in preclinical models of autoimmune disorders, organ fibrosis, and ischemia–reperfusion injury. However, their broader clinical translation is hindered by a critical paradox in oncology. While HIF-α can potentiate anti-tumor immunity, its sustained activation risks promoting malignancy by driving angiogenesis, metabolic reprogramming, and fostering an immunosuppressive tumor microenvironment. Addressing this duality, alongside the potential for long-term immune dysregulation, is paramount. Future development must therefore prioritize precision-targeting strategies to harness the therapeutic benefits of HIF-PHD inhibitors while mitigating their pro-tumorigenic liabilities.