Diffuse gliomas represent a heterogeneous group of universally lethal brain tumors characterized by minimally effective genotype-targeted therapies. Recent advances have revealed that a remarkable level of genetic, epigenetic, and environmental heterogeneity exists within each individual glioma. Together, these interconnected layers of intratumoral heterogeneity result in extreme phenotypic heterogeneity at the cellular level, providing for multiple mechanisms of therapeutic resistance and forming a highly adaptable and resilient disease. In this review, we discuss how glioma intratumoral heterogeneity and malignant cellular state plasticity drive resistance to existing therapies and look to a future in which these challenges may be overcome.

Glioma intratumoral heterogeneity and malignant cell state plasticity represent formidable hurdles to the development of novel targeted therapies. However, the convergence of genotypically diverse glioma cells into a limited set of epigenetically encoded transcriptional cell states may present an opportunity for a novel therapeutic strategy we call “State Selective Lethality.” In this approach, cellular states (as opposed to genetic perturbations/mutations) are the subject of therapeutic targeting, and plasticity-mediated resistance is minimized through the design of cell state “trapping agents.”