• Donald M Miller, Kavitha Yadanapudi, Veeresh Rai, Shesh N Rai, Joseph Chen, Hermann B Frieboes, Adrianna Masters, Abigail McCallum, and Brian J Williams.
• Brown Cancer Center, University of Louisville, Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, USA. Electronic address: donaldmi@ulh.org.
• Am. J. Med. Sci. 2023 Sep 1; 366 (3): 185198185-198.

AbstractGlioblastoma (GBM), the most common human brain tumor, has been notoriously resistant to treatment. As a result, the dismal overall survival of GBM patients has not changed over the past three decades. GBM has been stubbornly resistant to checkpoint inhibitor immunotherapies, which have been remarkably effective in the treatment of other tumors. It is clear that GBM resistance to therapy is multifactorial. Although therapeutic transport into brain tumors is inhibited by the blood brain barrier, there is evolving evidence that overcoming this barrier is not the predominant factor. GBMs generally have a low mutation burden, exist in an immunosuppressed environment and they are inherently resistant to immune stimulation, all of which contribute to treatment resistance. In this review, we evaluate the contribution of multi-omic approaches (genomic and metabolomic) along with analyzing immune cell populations and tumor biophysical characteristics to better understand and overcome GBM multifactorial resistance to treatment.Copyright © 2023 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

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