Neuroinflammation in Central Nervous System Tumors

Abstract

Highlights What are the main findings? Neuroinflammation in CNS tumors, especially glioblastoma, is an active driver of tumor progression, rather than a passive bystander, through coordinated interactions among myeloid cells, astrocytes, lymphocytes, and tumor cells within the microenvironment. Tumor-promoting inflammation is sustained by immunosuppressive signaling, metabolic reprogramming, and neuron–glioma communication, with distinct patterns across IDH-wildtype gliomas, IDH-mutant gliomas, and brain metastases. What are the implications of the main findings? Effective therapies will likely need to target several linked processes at once, including myeloid immunosuppression, metabolic adaptation, and bioelectric tumor-neural signaling, rather than relying on single-pathway approaches. Integrated biomarkers from imaging, liquid biopsy, and microenvironmental profiling may improve patient stratification and support the translation of emerging strategies such as CSF1R inhibition, immune checkpoint modulation, and next-generation cellular immunotherapy. Abstract Neuroinflammation within the tumor microenvironment (TME) of central nervous system (CNS) neoplasms, particularly glioblastoma (GBM), is no longer viewed merely as a reactive phenomenon but rather as a major driver of gliomagenesis and malignant transformation. This process involves a shift from acute immune activation to a chronic, sterile state that reshapes the CNS borders and immune niches to favor tumor evasion. This narrative review provides a comprehensive mechanistically focused analysis of the mechanisms governing the inflammatory stroma in primary and metastatic brain neoplasms. It critically examines the ontogeny and transcriptomic profile of myeloid and glial populations, dismantling the binary M1/M2 polarization model in favor of a continuum of functional states determined by metabolic and oxygenation gradients. It also analyzes intracellular signaling cascades, the subversion of innate immunity sensors such as the cGAS-STING pathway, the epigenetic reprogramming of stromal cells, and the role of extracellular vesicles. The electrochemical integration of tumor cells into neuronal circuits via glutamatergic synapses and connexin 43 gap junction coupling is addressed in detail, defining the mitogenic impact of neuronal activity on the tumor. The inflammatory profiles of IDH-wildtype and IDH-mutant gliomas and of secondary brain metastases are contrasted. Finally, the correlates of functional neuroimaging, liquid biopsies, and resistance mechanisms to conventional therapies are analyzed, including the GIANT and SENIPERA clinical trials, CARv3-TEAM-E bivalent cellular immunotherapy preconditioned with the LDC + R regimen, and the accelerated approval of dordaviprone (Modeyso) in H3 K27M-mutant diffuse midline gliomas.