Bioinformatics-driven dissection of PANoptosis-related molecular subtypes and tumor immune microenvironment heterogeneity in pediatric acute myeloid leukemia

PANoptosis, an integrated programmed cell death modality encompassing apoptosis, necroptosis, and pyroptosis, exerts pleiotropic effects on tumor immune surveillance and immune escape. However, the molecular mechanisms underlying PANoptosis in pediatric acute myeloid leukemia (AML) remain poorly elucidated. Here, we performed bioinformatic analyses of AML bone marrow transcriptomic data from the TARGET database, aiming to define PANoptosis-associated molecular subtypes, characterize tumor immune microenvironment (TIME) heterogeneity, and identify candidate regulatory genes and small-molecule binders. We identified 68 PANoptosis-related genes and used unsupervised clustering to resolve four molecular subtypes (C1-C4) with distinct clinical outcomes and TIME profiles. The C2 subtype exhibited robust CD8⁺ cytotoxic T-cell and natural killer (NK) cell activity linked to favorable prognosis, whereas the C1 subtype displayed immune suppression and poor survival. We identified an IGF1-CCL2-CCL4 gene set correlated with PANoptosis regulation and enriched in Toll-like receptor signaling. In silico molecular docking suggested SB216763 as a candidate ligand for these targets, though this requires experimental validation. Our findings outline PANoptosis-associated heterogeneity in pediatric AML and provide a stratification framework for future mechanistic and translational studies.