Current Understanding of Hypoxia in Glioblastoma Multiforme and Its Response to Immunotherapy

Abstract

Simple Summary Glioblastoma multiforme (GBM) is the most aggressive tumor type in the central nervous system. Hypoxia, defined as a lack of sufficient oxygen in tissues, is the most detrimental factor for the survival of GBM patients, promoting drug resistance, and invasion and inhibition of immune responses. Traditionally, tumor hypoxia has been studied from a narrow viewpoint, excluding the immune system and focusing primarily on the effect of hypoxia on blood vessels and tumor cells. More recently, however, evidence highlighting the important role of immunosurveillance has been uncovered for multiple tumors, including GBM. Thus, connecting the knowledge gained from traditional hypoxia studies with findings from recent immunological studies is urgently needed to better understand the role of hypoxia in cancer. Hypoxia is a hallmark of glioblastoma multiforme (GBM), the most aggressive cancer of the central nervous system, and is associated with multiple aspects of tumor pathogenesis. For example, hypoxia induces resistance to conventional cancer therapies and inhibits antitumor immune responses. Thus, targeting hypoxia is an attractive strategy for GBM therapy. However, traditional studies on hypoxia have largely excluded the immune system. Recently, the critical role of the immune system in the defense against multiple tumors has become apparent, leading to the development of effective immunotherapies targeting numerous cancer types. Critically, however, GBM is classified as a "cold tumor" due to poor immune responses. Thus, to improve GBM responsiveness against immunotherapies, an improved understanding of both immune function in GBM and the role of hypoxia in mediating immune responses within the GBM microenvironment is needed. In this review, we discuss the role of hypoxia in GBM from a clinical, pathological, and immunological perspective.