Neuroimmunology-driven CAR T-cell therapeutics for gliomas: translational challenges and clinical trial paradigm innovation

Glioma, a category of the most lethal primary brain tumors, remains incurable despite multimodal therapy combining maximal resection, radiation, and temozolomide. These interventions invariably fail due to residual invasive cells, molecular heterogeneity, and an immunosuppressive tumor microenvironment (TME) reinforced by myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). The blood-brain barrier (BBB) further limits therapeutic access, while antigen escape and T-cell exclusion mechanisms drive relapse. Chimeric antigen receptor (CAR) T-cell therapy, transformative in relapsed B-cell malignancies with sustained remission rates, faces formidable yet surmountable barriers in solid tumors. Recent advances in CAR-T trials targeting glioma-associated antigens demonstrate partial intracranial activity, albeit with transient efficacy, underscoring the need for neuroimmunology-informed engineering. This review critically evaluates CAR-T strategies countering glioma-specific resistance: bispecific antigen targeting combats tumor plasticity, cytokine-armored designs neutralize immunosuppression, and innovative delivery routes enhance CNS bioavailability. Early clinical outcomes reveal critical divergence points from hematologic success, including antigen loss due to glioma's evolutionary capacity and T-cell exhaustion within hypoxic niches. Emerging solutions integrate CRISPR-edited allogeneic platforms with combinatorial immunomodulation (e.g., myeloid-targeting) and delivery innovations to address these barriers. We further dissect translational priorities including neurotoxicity mitigation and scalable manufacturing for infiltrative glioma phenotypes. By converging advances in immune-engineering, TME remodeling, and biomarker-driven trial designs, this work proposes a roadmap to achieve durable CAR-T efficacy in GBM. The synthesis bridges mechanistic insights into glioma-immune interactions with clinical translation strategies, aiming to transcend current limitations of transient cytoreduction and establish CAR-T therapy as a cornerstone of neuro-oncologic practice.