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

Area of Science:

• Cancer Biology
• Systems Biology
• Immunology

Background:

• Therapy failure in non-small cell lung cancer (NSCLC) is linked to resistance to immunogenic cell death.
• The tumor suppressor p53 can initiate distinct pyroptosis pathways (canonical and secondary) with varying immunogenicity.
• The regulatory logic coordinating these parallel cell death pathways is not well understood.

Purpose of the Study:

• To develop the first dynamic Boolean network model of p53-regulated pyroptosis in NSCLC.
• To elucidate the systems-level logic governing the decision between canonical and secondary pyroptosis.
• To understand how these pathways influence therapeutic outcomes and immunogenicity in NSCLC.

Main Methods:

• Development of a dynamic Boolean network model of p53-regulated pyroptosis.
• Analysis of interlocked feedback loops governing the caspase-gasdermin axis.
• Validation of model predictions using NSCLC cell-line phenotypes and patient transcriptomics.

Main Results:

• The model identifies the terminal caspase-gasdermin axis as a bistable immunogenic switch.
• GSDME is identified as a critical fate-determining node, not merely an executioner.
• Loss of GSDME is predicted to reroute p53-activated caspase-3 towards apoptosis, explaining evasion of immunogenic lysis.
• Coordinated repression of pyroptosis genes and identification of CASP9/GSDME as adverse prognostic markers.

Conclusions:

• p53 acts as a central coordinator of a terminal cell fate-switch network.
• The study provides a systems-level framework for understanding cell death regulation in NSCLC.
• Findings offer insights into therapeutic strategies targeting cell death pathways for improved NSCLC treatment.