Reprogramming temozolomide response in glioblastoma through regulated and immunogenic cell death modalities.

Temozolomide (TMZ) resistance, driven by genetic, epigenetic, and tumor microenvironment factors, remains a significant barrier in glioblastoma (GBM) therapy. Immunogenic cell death (ICD) modalities (such as necroptosis, ferroptosis, pyroptosis) offer a promising strategy to overcome TMZ resistance by enhancing tumor immunogenicity and reducing adaptive resistance. A strategic shift from conventional TMZ-induced apoptosis to a mixed cell death approach may enhance GBM sensitivity and therapeutic outcomes. However, balancing ICD activation is critical to avoid unintended pro-tumorigenic effects. In this review, we critically evaluate TMZ's potential to induce multiple regulated cell death modalities, including apoptosis, necroptosis, ferroptosis, pyroptosis and cuproptosis, then map the detailed crosstalk between these regulated cell death pathways and assess their ICD characteristics. From a future perspective, we discuss the challenges associated with TMZ application in GBM therapy and propose novel strategies for developing highly effective GBM therapies and improving long-term treatment outcomes.