Killing with a purpose: harnessing immunological cell death in brain tumors

Primary and metastatic brain tumors remain among the most challenging malignancies to treat, with limited therapeutic options and poor clinical outcomes despite substantial advances in cancer immunotherapy. Although immune checkpoint blockade (ICB) and other immunotherapies have transformed the treatment landscape for many cancers, they have demonstrated only limited efficacy in brain tumors. This limited responsiveness reflects the unique immune landscape of the central nervous system (CNS), which restricts immune cell infiltration and is further shaped by a highly immunosuppressive tumor immune microenvironment (TIME) that suppresses effective antitumor immunity. Consequently, therapeutic strategies capable of enhancing tumor immunogenicity while overcoming local immune suppression are urgently needed. One promising approach is the induction of immunogenic cell death (ICD), a form of regulated cell death that stimulates anti-tumor immunity through the release of danger-associated molecular patterns (DAMPs), tumor antigens, and inflammatory cytokines and chemokines that promote immune activation. However, the ability of ICD to generate durable antitumor responses within brain tumors is therefore likely influenced by the complex immunosuppressive networks that characterize the brain TIME. In this review, we examine the major barriers to effective antitumor immunity within brain tumors, focusing on the immunosuppressive cellular and cytokine/chemokine molecular networks that shape the brain tumor immune microenvironment, the influence of tumor origin and subtype on immune composition, and the implications of these features for therapeutic responsiveness. We then discuss how ICD may help overcome these barriers by enhancing antigen presentation, immune cell recruitment, and adaptive immune priming. We review the principal ICD-associated cell death modalities, including ferroptosis, necroptosis, and pyroptosis, and summarize current therapeutic approaches capable of inducing these pathways in brain tumors, including radiotherapy, chemotherapy, targeted therapies, oncolytic viruses, and emerging nanomedicine-based strategies. Finally, we highlight clinical and preclinical evidence supporting ICD-relevant therapeutic approaches across glioblastoma (GBM) and brain metastases and discuss rational combination strategies may improve immune responsiveness and therapeutic outcomes in patients.