Glioblastoma (GBM) is the most lethal brain malignancy in adults and is associated with a poor prognosis. Therapy options in GBM patients are largely limited by the highly immunosuppressive tumor microenvironment (TME). Identifying and disrupting these immunosuppressive communication circuits between immune cells and the tumor is key to reinvigorate the immune system’s ability to fight the tumor. Here, we combine my previous experience in the analysis of single cell data at the neuro-immune interface with Prof. Zeiser’s patient-centered expertise in developing novel therapy options to combat tumor immune escape. In this highly complementary setting, we propose a data-driven approach to trace and perturb inhibitory communication circuits elicited by the TME across space and time with the aim to discover novel immunotherapeutic targets in GBM. Using a novel temporal single cell technology, we will 1) assemble a multi-layered spatio-temporal single cell roadmap to characterize and model how individual immune cells are affected by the TME in a murine model of GBM. 2) We will develop a computational framework for spatial transcriptomics to dissect single cells into niches defined by similar interaction programs with neighboring cells. 3) Using this tool, we will quantify the niche organization in human patients and identify ligand-receptor interaction pairs crucial for niche maintenance. 4) Candidate genes will be genetically ablated in either the tumor or the immune compartment and evaluated with regards to their in vivo efficacy in suppressing tumor growth. Our cutting-edge analytical pipeline from the identification of driver molecules for immune escape to the assessment of in vivo efficacy in a preclinical model of GBM will reveal novel targets for treatment. Our study thereby works directly towards the Horizon Europe Mission to understand, treat and beat cancer.