Regulatory networks of HIFs in tumor‑infiltrating immune cells: From molecular mechanisms to therapeutic implications (Review)

Hypoxic tumor microenvironment (TME) is a common occurrence in the development of solid tumors, which activates hypoxia‑inducible factors (HIFs) and their downstream signaling pathways in cancer cells to facilitate tumor progression and immune escape. However, among the various immune cells that constitute innate and adaptive immune systems, HIFs have a more intricate function; moreover, different isoforms of HIFs play different functions under spatial and temporal conditions. HIFs are conducive to the adaptation of various immune cells to the hypoxic TME. The stability of HIF‑α can regulate metabolism and directly regulate the expression of immune genes. Additionally, the activation of HIF signaling may also inhibit the development of immune cells in some tumor environments, affecting the antigen recognition and killing processes to assist cancer cells in immune escape. Therefore, understanding the relationship between HIF signaling and immune cells more comprehensively may yield substantial benefits for the immunotherapy of various types of cancer. The present study reviewed the role of HIFs in immunity, including their role in T cells, B cells, macrophages, neutrophils, dendritic cells and natural killer cells. It also discussed the effectiveness of HIF targeted therapy in clinical application, the challenges associated with it and the development of a precise targeting drug delivery system. The present review may help researchers comprehend the tumor immune process in a hypoxic microenvironment. It aimed to offer novel strategies for cancer immunotherapy and prolonging the overall survival of patients. .