Gut Microbiome Strategies for Enhancing ICI Delivery Across the BBB in Glioblastoma

ABSTRACT Glioblastoma (GB) is highly malignant with a median survival of 14 months despite conventional treatments like surgery, radiotherapy, and temozolomide. Resistance to these therapies necessitates innovative approaches, such as immune checkpoint inhibitors (ICIs) targeting cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4), programmed cell death protein 1 (PD‐1), and programmed death ligand 1 (PD‐L1) to enhance T‐cell‐mediated tumor destruction. However, clinical trials have shown limited ICI efficacy in GB due to its immunosuppressive microenvironment and the blood–brain tumor barrier (BBTB), which impairs drug delivery. Emerging evidence highlights the gut microbiota as a pivotal modulator of ICI response, enhancing CD8 + and CD4 + T‐cell function, antigen presentation, and immune modulation via the gut‐brain axis in cancers. In addition, studies showed that gut‐derived metabolites, including short‐chain fatty acids, modulate immune responses and support blood–brain barrier integrity by regulating inflammatory signaling and tight junction proteins. Future GB research should prioritize clinical trials, mechanistic studies, and interventional strategies like fecal microbiota transplantation and probiotics to enhance ICI efficacy.