2097 - Novel Insights into Cell Death Pathways in Esophageal Cancer Radiotherapy: A Strategic Framework Highlighting HMGB1 as Dual Prognostic Biomarker and Therapeutic Target

Purpose/Objective(s):

To systematically characterize radiotherapy-induced programmed cell death (PCD) landscapes in esophageal cancer (EC) and identify key molecular mediators linking radiosensitivity with immune regulation.

Materials/Methods:

A systematic PubMed review (2012-2022) identified experimentally validated PCD regulators (318 studies), from which an interaction network of 13 core genes was constructed. Dose–time thresholds for autophagy were defined using preclinical evidence. Transcriptomic data from GSE137867 (pre- vs post-radiotherapy EC samples) were analyzed to identify differentially expressed genes and enriched pathways. HMGB1, identified as a network hub, was further validated using TCGA-ESCA for expression, survival, and clinicopathologic associations. Immune infiltration and immune-checkpoint correlations were assessed using TIMER2.0.

Results:

Protective autophagy predominated at 2-8 Gy within 4-24 h, whereas higher doses or prolonged exposure promoted autophagic cell death. Differentially expressed genes were enriched in mitotic and NF-?B related pathways. HMGB1 was significantly upregulated in tumors, associated with advanced T stage and poorer overall survival, and displayed distinct correlations with immune-cell infiltration and PD-L1 expression.

Conclusion:

This integrative analysis delineates PCD-specific dose–time windows in EC radiotherapy and identifies HMGB1 as a prognostic and immunomodulatory mediator, offering a precision-oriented framework for optimizing radiotherapy and combinatorial PCD-targeted strategies