Resistance to programmed cell death (PCD) is a hallmark of cancer. While some PCD components are prognostic in cancer, the roles of many molecules can be masked by redundancies and crosstalks between PCD pathways, impeding the development of targeted therapeutics. Recent studies characterizing these redundancies have identified PANoptosis, a unique innate immune-mediated inflammatory PCD pathway that integrates components from other PCD pathways. Here, we designed a systematic computational framework to determine the pancancer clinical significance of PANoptosis and identify targetable biomarkers. We found that high expression of PANoptosis genes was detrimental in low grade glioma (LGG) and kidney renal cell carcinoma (KIRC). and expression consistently had negative effects on prognosis in LGG across multiple survival models, while and expression had negative effects for KIRC. Conversely, high expression of PANoptosis genes was beneficial in skin cutaneous melanoma (SKCM), with and expression consistently having positive prognostic effects. As a therapeutic proof-of-concept, we treated melanoma cells with combination therapy that activates ZBP1 and showed that this treatment induced PANoptosis. Overall, through our systematic framework, we identified and validated key innate immune biomarkers from PANoptosis which can be targeted to improve patient outcomes in cancers.