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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.
Wang et al. (Fri,) studied this question.