Unlocking glioma vulnerabilities: targeting regulated cell death pathways for innovative therapies

Glioma, the most prevalent primary brain tumor, primarily arises from glial cells or their progenitors. Histologically, gliomas are classified into astrocytomas, oligodendrogliomas, and ependymomas. Due to their aggressive invasive nature and resistance to chemotherapy, gliomas exhibit high recurrence rates and poor clinical outcomes. Regulated cell death (RCD) refers to a set of genetically controlled cellular processes that significantly influence tumor behavior. RCD plays a dual role in cancer: under normal physiological conditions, it eliminates malignant cells to prevent tumorigenesis, while in pathological conditions, tumor cells evade RCD to gain survival advantages. Furthermore, distinct RCD pathways can modulate the tumor immune microenvironment, thereby affecting therapeutic outcomes. Targeting RCD mechanisms presents a promising strategy to overcome therapeutic resistance and advance innovative glioma immunotherapies. This review explores the molecular mechanisms of pyroptosis, ferroptosis, necroptosis, and autophagy in glioma, emphasizing their critical roles in tumor progression. It also examines therapeutic strategies targeting RCD, including recent advancements in glutathione peroxidase 4 (GPX4) inhibitors, oncolytic virotherapy, and other emerging agents. Furthermore, the review discusses the potential of nanoparticle-based drug delivery systems and multi-omics approaches to optimize personalized combination therapies, aiming to enhance multimodal, synergistic interventions for more effective glioma management.