| Summary: | Abstract Hypoxia, which activates a variety of signaling pathways to enhance tumor cell growth and metabolism, is among the primary features of tumor cells. Hypoxia-inducible factors (HIFs) have a substantial impact on a variety of facets of tumor biology, such as epithelial-mesenchymal transition, metabolic reprogramming, angiogenesis, and improved radiation resistance. HIFs induce hypoxia-adaptive responses in tumor cells. Many academics have presented preclinical and clinical research targeting HIFs in tumor therapy, highlighting the potential applicability of targeted HIFs. In recent years, the discovery of numerous pharmacological drugs targeting the regulatory mechanisms of HIFs has garnered substantial attention. Additionally, HIF inhibitors have attained positive results when used in conjunction with traditional oncology radiation and/or chemotherapy, as well as with the very promising addition of tumor immunotherapy. Immune checkpoint inhibitors (CPIs), which are employed in a range of cancer treatments over the past decades, are essential in tumor immunotherapy. Nevertheless, the use of immunotherapy has been severely hampered by tumor resistance and treatment-related toxicity. According to research, HIF inhibitors paired with CPIs may be game changers for multiple malignancies, decreasing malignant cell plasticity and cancer therapy resistance, among other things, and opening up substantial new pathways for immunotherapy drug development. The structure, activation mechanisms, and pharmacological sites of action of the HIF family are briefly reviewed in this work. This review further explores the interactions between HIF inhibitors and other tumor immunotherapy components and covers the potential clinical use of HIF inhibitors in combination with CPIs.
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