p53 Orchestrates the Immunogenic-Tolerogenic Pyroptosis Switch in Non-Small Cell Lung Cancer: A Systems Biology Approach

Resistance to immunogenic cell death drives therapy failure in non-small cell lung cancer (NSCLC). While the tumor suppressor p53 can activate both canonical (NLRP3–caspase-1–GSDMD) and secondary (caspase-9/3–GSDME) pyroptosis, 2 lytic programs with divergent immunogenicity, the systems-level logic coordinating these parallel execution pathways remains unknown, limiting therapeutic exploitation. Here, we deploy, to our knowledge, the first dynamic Boolean network model of p53-regulated pyroptosis in NSCLC to resolve this decision layer. The model suggests that the terminal caspase–gasdermin axis may be structured as a bistable immunogenic switch, governed by interlocked feedback loops: a double-negative motif (caspase-9–caspase-3–GSDMD) that enables mutual exclusivity and a reinforcing loop (GSDME–caspase-9–caspase-3) that commits to secondary pyroptosis. Within the model, this topology positions GSDME not as a passive executioner but as a critical fate-determining node; its loss, frequent in NSCLC, does not abort death signaling but is predicted to re-route p53-engaged caspase-3 activity toward apoptosis, providing a potential explanation for how tumors may evade immunogenic lysis while retaining apoptotic competence. Model predictions are validated against NSCLC cell-line phenotypes and patient transcriptomics, revealing coordinated repression of pyroptosis-execution genes and identifying CASP9/GSDME as adverse prognostic markers. Collectively, our results suggest that p53 functions as a central coordinator of a terminal fate-switch network rather than a simple linear activator and provide a systems-level framework for investigating how execution-layer regulatory circuits influence cell-death outcomes in NSCLC.