Understanding the brain tumor microenvironment: Considerations to applying systems biology and immunotherapy

Patients with malignant brain cancers such as glioblastoma and brain metastases (BM) represent a population with a large unmet medical need, and a multitude of drugs have failed over decades. The current treatment modalities include surgery, radiation, and chemotherapy; yet, the median survival of patients with gliomas and BM remains abysmally low at 15 months and 2–14 months, respectively. In addition, standard treatments cause debilitating motor and neurological deficits. The paucity of effective therapies, despite intense investigation over the past several decades, represents inherent challenges to treating brain cancer and the critical knowledge gap in understanding tumor sensitivity, drug delivery, and microenvironmental shifts. Recently, immunotherapy has shown tremendous efficacy in melanoma and other cancers but has yet to revolutionize the treatment of brain cancers. However, as immunotherapy holds the promise of specifically targeting and eliminating tumor cells while sparing normal brain cells, innovative methods for investigating immunotherapy for brain cancer are essential for optimizing patient response. In this review, we will summarize the key issues and how a systems biology approach can help decipher this complexity and lead to better understanding and therapeutic targeting of the brain cancers.