Review: therapeutic approaches for circadian modulation of the glioma microenvironment

Front Oncol. 2023 Dec 20:13:1295030. doi: 10.3389/fonc.2023.1295030. eCollection 2023.


High-grade gliomas are malignant brain tumors that are characteristically hard to treat because of their nature; they grow quickly and invasively through the brain tissue and develop chemoradiation resistance in adults. There is also a distinct lack of targeted treatment options in the pediatric population for this tumor type to date. Several approaches to overcome therapeutic resistance have been explored, including targeted therapy to growth pathways (ie. EGFR and VEGF inhibitors), epigenetic modulators, and immunotherapies such as Chimeric Antigen Receptor T-cell and vaccine therapies. One new promising approach relies on the timing of chemotherapy administration based on intrinsic circadian rhythms. Recent work in glioblastoma has demonstrated temporal variations in chemosensitivity and, thus, improved survival based on treatment time of day. This may be due to intrinsic rhythms of the glioma cells, permeability of the blood brain barrier to chemotherapy agents, the tumor immune microenvironment, or another unknown mechanism. We review the literature to discuss chronotherapeutic approaches to high-grade glioma treatment, circadian regulation of the immune system and tumor microenvironment in gliomas. We further discuss how these two areas may be combined to temporally regulate and/or improve the effectiveness of immunotherapies.

Keywords: chronotherapy; circadian; glioblastoma; glioma; pediatric high-grade glioma; tumor microenvironment (TME).

Publication types

  • Review

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was funded by the DIPG DMG Research Funding Alliance (DDRFA to LP and EG), Chambers-Okamura Faculty Scholar in Pediatric Neurosurgery (LP), Shurl and Kay Curci Foundation Award (LP), and the Stanford Medical Scholars Research fellowship program (EN).