Tumor‐Associated Macrophages Nano‐Reprogrammers Induce “Gear Effect” to Empower Glioblastoma Immunotherapy

Abstract Glioblastoma (GBM), the most malignant brain tumor with high prevalence, remains highly resistant to the existing immunotherapies due to the significant immunosuppression within tumor microenvironment (TME), predominantly manipulated by M2‐phenotypic tumor‐associated macrophages (M2‐TAMs). Here in this work, an M2‐TAMs targeted nano‐reprogrammers, MG5‐S‐IMDQ, is established by decorating the mannose molecule as the targeting moiety as well as the toll‐like receptor (TLR) 7/8 agonist, imidazoquinoline (IMDQ) on the dendrimeric nanoscaffold. MG5‐S‐IMDQ demonstrated an excellent capacity of penetrating the blood‐brain barrier (BBB) as well as selectively targeting M2‐TAMs in the GBM microenvironment, leading to a phenotype transformation and function restoration of TAMs shown as heightened phagocytic activity toward tumor cells, enhanced cytotoxic effects, and improved tumor antigen cross‐presentation capability. In the meantime, by induction of a function‐oriented “gear effect”, MG5‐S‐IMDQ treatment extended its impact systemically by enhancing the infiltration of type I conventional dendritic cells (cDC1s) into the tumor sites and bolstering adaptive immune responses. In sum, by precisely working on M2‐TAMs as a unique target in tumor situ, the nano‐reprogrammers successfully established a robust immune network that worked synergistically to combat tumors. This facile nanoplatform‐based immunomodulatory strategy, serving as a powerful and convenient immune monotherapy or as a complementary treatment alongside other therapies like surgery, provided deep insights for advancing translational study in GBM.