Exploring Novel Compounds and Nanocomplexes to Target Cellular and Molecular Interactions in the Glioblastoma Microenvironment

Glioblastoma is the most lethal primary brain tumor, characterized by a profoundly immunosuppressive microenvironment. This stroma includes various immunosuppressive and tumor-killing cells. This review critically evaluates emerging strategies for reprogramming the glioblastoma microenvironment to restore antitumor immunity. We focus on novel small molecules, natural products, adjuvants, and nanomedicine platforms that can remodel immunosuppressive microenvironment of glioblastoma. Preclinical studies demonstrate that therapy modalities can induce various forms of cell death and the release of danger signals that not only stimulate immunogenic responses but also cause the regulation of checkpoint molecules. In addition, several cytokines and danger signals can stimulate signal transducer and activator of transcription 3 (STAT3) and nuclear factor of κappa B (NF‑κB) in cancer and immune cells. These factors not only enhance resistance to apoptosis but also boost immunosuppressive responses. Targeting cancer-associated fibroblasts (CAFs) and their specific secretions, reprogramming marcrophages using colony-stimulating factor-1 (CSF-1) inhibitors or toll-like receptor (TLR) agonists, depleting myeloid cells through chemokine receptor blockade, and disrupting metabolic suppression can each partially remodel glioblastoma microenvironment. Nanocomplexes improve brain delivery and enable multimodal drug co-delivery. However, clinical translation has been disappointing for checkpoint inhibitors in phase III trials. Furthermore, myeloid-targeted agents have shown limited efficacy because of the profound plasticity and redundancy of the glioblastoma microenvironment. Effective immunotherapy for glioblastoma will require rationally designed multimodal combinations that simultaneously target the stromal barriers, the immunosuppressive milieu, and the exhausted state of T cells. Emerging strategies such as oncolytic viruses engineered to express immunomodulatory payloads and biomarker-guided adaptive trial designs can be promising for future studies.