Dual‐Function Lipid‐Based Nanovector Strategy for Glioblastoma Immunotherapy: STING Activation and M1 Microglia Polarization

Abstract

Glioblastoma (GBM) remains one of the most lethal brain malignancies because of its highly immunosuppressive tumor microenvironment and the limited penetration of therapeutics across the blood-brain barrier (BBB). Although recent studies have separately explored STING agonism, microglial reprogramming, and nanocarrier-based drug delivery, an integrated framework combining these strategies for GBM immunotherapy is still lacking. In this review, we present a new dual-function lipid-based nanovector (LNV) strategy that simultaneously activates the cGAS-STING pathway and induces tumor-associated microglia to repolarize toward the antitumor M1 phenotype. In contrast to previous reviews, which address them as individual approaches, herein we consolidate these into an integrated therapeutic paradigm and provide a rational design roadmap based on drug cargo selection, lipid isoform composition, BBB targeting, and thermo-/magnetically responsive release. We summarize how STING activation enhances type I interferon signaling, dendritic cell maturation, and cytotoxic T-cell priming, while M1-polarized microglia potentiate local inflammatory and phagocytic antitumor responses. In addition, we summarize the current nanocarrier platforms, preclinical evidence, and translational design considerations pertinent to this combinatorial approach. This review provides a conceptually integrated overview of the potential of dual-action lipid nanovectors to overcome clinically relevant immunological and delivery barriers in GBM, as well as future directions for next-generation nano-immunotherapies.