| Summary: | In recent years, the direct interaction between cancer cells and tumor microenvironment (TME) has emerged as a crucial regulator of tumor growth and a promising therapeutic target. The TME, including the surrounding peritumoral regions, is dynamically modified during tumor progression and in response to therapies. However, the mechanisms regulating the crosstalk between malignant and non-malignant cells are still poorly understood, especially in the case of glioma, an aggressive form of brain tumor. The presence of unique brain-resident cell types, namely neurons and glial cells, and an exceptionally immunosuppressive microenvironment pose additional important challenges to the development of effective treatments targeting the TME. In this review, we provide an overview on the direct and indirect interplay between glioma and neuronal and glial cells, introducing new players and mechanisms that still deserve further investigation. We will focus on the effects of neural activity and glial response in controlling glioma cell behavior and discuss the potential of exploiting these cellular interactions to develop new therapeutic approaches with the aim to preserve proper brain functionality.
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