This study explores the synergistic antitumor effects of oncolytic HSV-1 (oHSV) and Fusobacterium nucleatum outer membrane vesicles (Fn-OMV). oHSV induces ZBP1-mediated PANoptosis, a form of inflammatory programmed cell death, which enhances antitumor immunity by releasing inflammatory signals and tumor antigens. Mechanistically, oHSV increases the expression of interferon-stimulated genes, leading to the accumulation of endogenous Z-RNA, which activates ZBP1. Fn-OMV further enhances this process by upregulating PANoptosis execution proteins such as GSDMD/E and MLKL through interference with ubiquitination. The combination of oHSV and Fn-OMV significantly improves antitumor immune responses, converting "cold" tumors into "hot" tumors and enhancing the efficacy of immunotherapy. The study demonstrates that oHSV-induced PANoptosis is crucial for antitumor immunity, and the combination with Fn-OMV enhances this effect by boosting the expression of key PANoptosis proteins. This strategy shows promise for improving cancer treatment by leveraging innate immune mechanisms and enhancing immune responses. The findings highlight the potential of combining viral and bacterial therapies to enhance antitumor immunity and improve therapeutic outcomes.This study explores the synergistic antitumor effects of oncolytic HSV-1 (oHSV) and Fusobacterium nucleatum outer membrane vesicles (Fn-OMV). oHSV induces ZBP1-mediated PANoptosis, a form of inflammatory programmed cell death, which enhances antitumor immunity by releasing inflammatory signals and tumor antigens. Mechanistically, oHSV increases the expression of interferon-stimulated genes, leading to the accumulation of endogenous Z-RNA, which activates ZBP1. Fn-OMV further enhances this process by upregulating PANoptosis execution proteins such as GSDMD/E and MLKL through interference with ubiquitination. The combination of oHSV and Fn-OMV significantly improves antitumor immune responses, converting "cold" tumors into "hot" tumors and enhancing the efficacy of immunotherapy. The study demonstrates that oHSV-induced PANoptosis is crucial for antitumor immunity, and the combination with Fn-OMV enhances this effect by boosting the expression of key PANoptosis proteins. This strategy shows promise for improving cancer treatment by leveraging innate immune mechanisms and enhancing immune responses. The findings highlight the potential of combining viral and bacterial therapies to enhance antitumor immunity and improve therapeutic outcomes.