Hypoxia as a Potential Inducer of Immune Tolerance and a Driver of Tumor Mutational Burden: Impact on Cancer Immunotherapy

In cancer patients, immune cells are often functionally compromised due to the immunosuppressive features of the tumor microenvironment (TME) which contributes to the failures in cancer therapies, including immunotherapy. Targeting immune systems can benefit patients across a wide range of tumors and immune checkpoint blockers drive current revolution in immunotherapy across multiple tumor types. Nevertheless, most cancer patients do not respond, and the determinants of response and resistance are not well understood. To survive, developing tumors adapt to the immunological environment and create a local microenvironment that inhibits immune function by inducing immune tolerance and invasion. The TME is an integral part of tumor physiology that nurtures the malignant process. In this context, microenvironmental hypoxia, which is a hallmark of solid tumors, may result in pleiotropic effects contributing significantly to tumor aggressiveness and therapy resistance. It controls tumor resistance and plasticity and promotes the differentiation and expansion of immune-suppressive stromal cells. More importantly, hypoxia also drives genomic instability in cancer cells, and it may hinder the DNA damage response and DNA repair. Recent advances place hypoxia as a potential driver of tumor mutational burden. Here, we review the current knowledge on how hypoxic stress in the TME impacts on the tumor heterogeneity, plasticity and immune resistance, with a special interest in tumor immunogenicity. A detailed and integrated understanding of the dual effect of hypoxia might lead to innovative approaches for accurately exploiting hypoxia-associated pathways in the clinical setting.