Glioblastoma (GBM), the most common primary malignant brain tumor, presents a daunting challenge in clinical management, with a meager 5-year survival rate of merely 5% [1]. Despite advancements in treatment modalities such as surgery, radiation, and chemotherapy, the prognosis remains dismal due to tumor heterogeneity and the intricate interplay between tumor cells and normal brain tissue, compounded by the impermeable blood-brain barrier.

Conventional therapies, including surgical resection, radiotherapy, and chemotherapy, have shown limited efficacy, resulting in high relapse rates and poor patient outcomes [2]. Therefore, there is an urgent need for innovative therapeutic approaches to combat GBM effectively.

Chimeric Antigen Receptor T (CAR-T) cell therapy, heralded for its success in hematological malignancies, has emerged as a promising avenue for solid tumors like GBM [3]. However, its application faces formidable challenges posed by the unique anatomical features of GBM, including the blood-brain barrier and the immunosuppressive tumor microenvironment, alongside tumor heterogeneity.

CAR-T therapy involves the extraction of T lymphocytes from the patient’s peripheral blood, genetic modification to express chimeric antigen receptors targeting specific tumor antigens, and reinfusion into the patient, thereby harnessing the immune system to target and destroy cancer cells [4].

The manufacturing process of CAR-T cells entails several meticulous steps, including T cell isolation, genetic engineering to introduce CAR genes, in vitro activation and expansion, and rigorous quality assessment before clinical administration [5].

While CAR-T therapies have demonstrated remarkable efficacy in hematologic malignancies, their application in solid tumors has been limited. The complexity of solid tumors, characterized by diverse cell populations, presents challenges in achieving sustained therapeutic responses [6].

Innovative strategies combining CAR-T therapy with bispecific antibodies, such as T-cell Engaging Antibody Molecules (TEAMs), hold promise in overcoming the hurdles posed by tumor heterogeneity [7]. These approaches aim to enhance the specificity and potency of CAR-T cells against solid tumors like GBM.

Recent clinical studies have reported encouraging outcomes with CAR-T therapy in GBM patients, demonstrating reduced tumor sizes and prolonged survival [8]. Notably, early-phase trials employing dual-target CAR-T cells, engineered to recognize multiple tumor-associated antigens, have shown promising results in shrinking tumors and extending patient survival [9].

Despite the progress, CAR-T cell therapy in GBM is not without limitations, with treatment-associated toxicities, including cytokine release syndrome and central nervous system complications, warranting careful monitoring and management [10].

In conclusion, the innovative field of CAR-T cell therapy is at the forefront of transforming the treatment paradigm for glioblastoma multiforme (GBM). The journey from preclinical studies to clinical trials has been fraught with challenges, yet these hurdles have been instrumental in uncovering and addressing the complexities of successful cancer treatment. The advent of CAR T cells equipped with multivalent receptors, combined with cutting-edge therapies, is tackling the problem of antigen escape [11]. Furthermore, the synergy of CAR T cell therapy with other treatments, such as immunotherapies, chemotherapies, or mechanical tumor ablation, is poised to foster a more inflammatory microenvironment conducive to better patient outcomes [11]. As research continues to refine these therapeutic strategies, there is a growing hope for significant advancements in the battle against this formidable disease.