Activating ZBP1-centered PANoptosis and a collaborative innate-adaptive immune response sensitizes glioblastoma to PD-1 blockade.

Glioblastoma is an immunologically cold, treatment-refractory brain tumor in which a profoundly immunosuppressive microenvironment drives resistance to immunotherapy. Retrospective clinical series reporting unexpectedly prolonged survival after postoperative intracranial infections raise the possibility that a brief, spatially confined inflammatory burst within the central nervous system can mitigate this resistance. Tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ) are central inflammatory cytokines, yet how to harness such cytokine-rich inflammatory signaling in glioblastoma remains unclear. Here, integrating multi-omics, high-dimensional immune profiling, and orthotopic models, we show that TNFα plus IFNγ triggers immunogenic PANoptosis and reprograms the tumor microenvironment. Co-stimulation induces a fused pyroptosis-apoptosis-necroptosis program, increases calreticulin exposure and extracellular release of adenosine triphosphate and high-mobility group box 1, and shifts tumor-associated microglia and macrophages toward a pro-inflammatory, antigen-presenting state with enhanced effector and memory T-cell infiltration and activation. Mechanistically, IFNγ-STAT1-IRF1 signaling primes Z-DNA binding protein 1 (ZBP1), whereas TNFα induces SLC39A1-dependent zinc accumulation, oxidative stress, and Z-form nucleic acids that engage ZBP1 to assemble the PANoptosome and execute PANoptosis. In vivo, local intratumoral TNFα+IFNγ delivery suppresses tumor growth, prolongs survival, and restores responsiveness to PD-1 blockade. A liposomal formulation co-encapsulating zinc and IFNγ recapitulates this circuitry while avoiding systemic TNFα exposure and further improves checkpoint efficacy. These findings position ZBP1-centered PANoptosis as a druggable signaling node linking inflammatory and metal-ion cues to immune reprogramming and immunotherapy sensitization in Glioblastoma.