Astrocyte-associated immunosuppressive programs in brain tumors: a STAT3-centered perspective

Astrocytes are increasingly recognized as important contributors to the immunosuppressive tumor microenvironment in glioblastoma and brain metastases. Rather than acting in isolation, tumor-associated astrocytes interact with tumor cells, myeloid populations, and vascular components to shape local immune dysfunction. Here, we propose modular immunosuppressive hubs (MISH) as an astrocyte-centered conceptual framework to describe how distinct suppressive programs may be organized within established tumor niches, with particular emphasis on STAT3-centered signaling. This review systematically deconstructs the composition, spatial regulation, and signaling output of these modules, highlighting how they mediate critical cell-cell communication within the TME. We further emphasize emerging pharmacological strategies aimed at dismantling MISH by targeting these specific signaling pathways, thereby reprogramming TAAs from immunosuppressive barriers into potential allies for immunotherapy. Targeting MISH signaling networks represents a promising avenue to overcome resistance to current immunotherapies and improve outcomes for patients with brain tumors.