Introduction: Glioblastoma multiforme (GBM) is the most common invasive brain tumor composed of diverse cell types with poor prognosis. The highly complex tumor microenvironment (TME) and its interaction with tumor cells play important roles in the development, progression, and durability of GBM. Angiogenic and immune factors are two major components of TME of GBM, their interplay is a major determinant of tumor vascularization, immune profile, as well as immune unresponsiveness of GBM. Given the ineffectiveness of current standard therapies (surgery, radiotherapy, and concomitant chemotherapy) in managing patients with GBM, it is necessary to develop new ways of treating these lethal brain tumors. Targeting TME, altering tumor ecosystem may be a viable therapeutic strategy with beneficial effects for patients in their fight against GBM.

Methods: Given the potential therapeutic effects of cannabidiol (CBD) in a wide spectrum of diseases including malignancies, we tested for the first time, whether inhalant CBD can inhibit GBM tumor growth using a well-established orthotopic murine model. Optical imaging, histology, immunohistochemistry, and flow cytometry were employed to document the outcomes.

Results: Our findings showed that inhalant CBD was able to limit not only the tumor growth, but also to alter the dynamics of TME by repressing P-selectin, apelin, and IL-8, as well as blocking a key immune checkpoint — indoleamine 2,3 dioxygenase (IDO). In addition, CBD enhanced the CD103 expression, indicating improved antigen presentation, promoted CD8 immune responses, and reduced innate Lymphoid Cells (ILCs) within the tumor.

Conclusion: Overall, our novel findings support the possible therapeutic role of inhalant CBD as an effective, relatively safe and easy to administer treatment adjunct for GBM with significant impacts on the cellular and molecular signaling of TME, warranting further research.