Abstract Glioblastoma (GBM), an incurable brain tumor, necessitates surgery followed by chemoradiation, but recurrences remain fatal. While regenerative responses post-tumor debulking aid healing, they also trigger time-dependent immune reactions promoting recurrence onset at resection cavity borders. Our prior work demonstrated that a nanomedicine hydrogel (GemC 12 -LNC) delays recurrence onset when administered post-surgery. Combining it with an immunomodulatory drug is hypothesized to enhance therapeutic outcomes. However, the post-surgical microenvironment (SMe) lacks proper characterization, hindering the development of combinatory therapies. In this study, we examined the impact of surgery on the brain and SMe, aiming to identify time frames and therapeutic targets for combinatory approaches. Blood and magnetic resonance images of GBM patients pre- and post-surgery were analyzed to understand the systemic immune response and blood-brain barrier (BBB) permeability changes following tumor debulking. Additionally, a mouse model of tumor resection was utilized for longitudinal SMe characterization through various imaging and analytical techniques. Dynamics of immune cell recruitment and localization from the brain parenchyma or periphery were examined. Transient BBB disruption post-surgery, recovering within a week, provided a systemic treatment window. Differences in immune cell composition, morphology, and spatial localization between unresected and resected tumors were identified, highlighting overexpression of pro-tumoral macrophages, border-associated macrophages and reactive microglia in resected tumors. Combining local GemC 12 -LNC with systemic SMAC-mimetic drug reversed this immune response, delaying post-surgical recurrence onset and increasing overall survival in GBM-bearing mice. This comprehensive study identified SMe time frames and immune cellular targets, facilitating the design of a rational combinatory treatment to delay recurrence onset.