Targeting HIF as a Promising Approach to Synergize With Immune Checkpoint Inhibitors

In solid tumors, hypoxia-inducible factor (HIF) is upregulated in various cell types within the tumor microenvironment (TME) due to hypoxia. In tumor cells, HIF signaling acts as a primary driver: it triggers metabolic reprogramming toward the Warburg effect and upregulates various angiogenic factors to support adaptation to hypoxia. Meanwhile, it promotes malignant progression by regulating cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling. In immune cells, HIF signaling precisely regulates the abundance and function of various immune cell subsets, thereby establishing an immunosuppressive microenvironment that enables tumor cells to evade immune surveillance. Ultimately, HIF signaling in different cell types acts in concert and constitutes a key factor that attenuates the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Over the decades of the development of HIF inhibitors, the antitumor effects of a large number of these agents have been validated in preclinical studies, with some having entered clinical trials or obtained clinical approval. Although only a small subset of HIF inhibitors has been verified to exert synergistic effects when combined with ICIs in experimental settings, it is undeniable that HIF inhibitors have emerged as a crucial "reserve force" for overcoming ICI resistance. Their potential in reshaping the immune microenvironment and enhancing the efficacy of ICIs provides a new direction for the immunotherapy of hypoxic solid tumors.