Strategies to Target Hypoxia-Induced Immune Suppression and Immune Escape Mechanisms

Hypoxia is a characteristic feature of the tumor microenvironment (TME), which makes cancer immunotherapy more difficult because it is necessary for immune escape and immunological suppression. Strategies to counter immunological escape routes in tumors and target hypoxia-induced immune suppression are covered in detail in this chapter. This chapter elucidates the manner hypoxia affects immune cell function, helps regulatory T cells (Tregs) proliferate, and triggers the expression of immunological checkpoint molecules like programmed death-ligand 1 (PD-L1). The chapter additionally examines how hypoxia contributes to an immunosuppressive TME by attracting myeloid-derived suppressor cells (MDSCs) and polarizing macrophages toward an immunosuppressive phenotype. To address these challenges, we review a range of therapeutic approaches. These include a range of hypoxia-activated prodrugs (HAPs) that selectively target hypoxic tumor cells and the development of agents that disrupt hypoxia-inducible factor (HIF) pathways. The potential of combining these therapies with immune checkpoint inhibitors (ICIs) to enhance anti-tumor immunity is also discussed. To further enhance the accuracy of targeting and effectiveness of these treatments, we investigate the use of delivery systems based on nanotechnology. The chapter stresses that in order to create effective treatment regimens, it is critical to understand the complex connections between immune escape mechanisms and hypoxia. By merging insights from preclinical research and clinical trials, we comprehensively evaluate existing and novel approaches to lessen immunological escape and mitigate hypoxia-induced immune suppression. Eventually, this means that immunotherapies for the treatment of cancer may be more successful.