The glioma microenvironment and its impact on antitumor immunity

Gliomas are a heterogeneous group of intrinsic brain tumors that are among the most difficult cancers to treat. Diffuse invasion into normal brain tissue prevents complete surgical resection; therefore, adjuvant therapy is necessary to curtail tumor progression and recurrence. High-grade, isocitrate dehydrogenase wild-type gliomas, also known as glioblastomas, are particularly resistant to treatment. Despite aggressive therapy with maximal safe resection, radiation, and chemotherapy, the median survival remains less than 2 years and has changed little in the past 2 decades. A major focus of therapeutic development for cancer treatment is immunotherapy, which aims to enhance the immune system's ability to destroy tumor cells wherever they reside. While cancer immunotherapy has dramatically improved outcomes for patients with advanced melanoma, lung cancer, and many other malignancies, immunotherapies have not yet demonstrated the ability to reliably improve survival for glioblastoma patients. One of the fundamental challenges to developing effective immunotherapy for glioblastoma is the heterogenous and complex tumor microenvironment (TME), where there are multiple anatomic, molecular, and functional barriers to generating and sustaining antitumor immunity. Recent insights into the contributions of specific components of the glioma tumor microenvironment are leading the way from a trial-and-error approach to rationally targeted combination therapies. In this focused review, we discuss specific characteristics of the TME that impede immunotherapy for glioma and approaches in various stages of development aimed at overcoming these barriers.