PANoptosis represents a coordinated and balanced process, defined as the concomitant activation of pyroptosis, apoptosis and necroptosis within the same cell population. Emerging evidence connects PANoptosis dysregulation with tumorigenesis, progression and therapy resistance. Zhu et al. identify cellular populations and prognostic biomarkers linked to PANoptosis and tumor progression in osteosarcoma (OS). The authors reveal that alterations in PANoptosis contributes to osteoblastic differentiation and tumor development, with osteoblast-lineage cells enriched in OS samples exhibiting low PANoptosis scores. Consequently, in patients with poor outcomes, prognostic biomarkers (CPE, SERPINH1, and NPW) are overexpressed, with CPE playing a dominant role. CPE is co-expressed with osteogenic genes in OS and is associated with bone defects. In addition, CPE promotes tumor growth, migration, invasion and epithelial-mesenchymal transition through activation of Wnt/β-catenin signalling. Moreover, consistent with literature showing that increased infiltration of M2-like tumor-associated macrophages is associated with OS metastasis and poor prognosis, the authors show a positive correlation between CPE expression and macrophage infiltration in OS. The study also finds a positive correlation between CPE and HYOU1 via activation of the Hippo-YAP signaling pathway. CPE-mediated stabilization of HYOU1 promotes YAP nuclear accumulation, suppresses PANoptosis (pyroptosis, apoptosis, and necroptosis), and enhances cellular survival. In vivo studies show that CPE silencing leads to suppressed tumor volume, tumor weight and Ki67 expression in tumor tissue. However, in vitro models and xenografts may not recapitulate the complexity of the bone microenvironment, limiting the clinical application of CPE-target therapies. In conclusion, further investigations are necessary to evaluate the prognostic potential of CPE and its role in pulmonary metastasis.