3092 - NLRP3 Inflammasome-Mediated Residual Tumor Cell Repopulation Promotes Radioresistance in Gastric Cancer

05:00pm - 06:00pm PT

Hall F

Screen: 23

Presenter(s)

Shuyan Li, PhD - Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, Shanghai

S. Li¹, W. Qi¹, S. Zhao¹, G. Cai¹, J. Chen¹, X. Wang², and X. Zhang²; ¹Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China, ²Department of Pathology, Ruijin Hospital and College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China

Purpose/Objective(s): Radiotherapy is a cornerstone treatment for gastric cancer, yet radioresistance remains a significant challenge. Tumor cell repopulation plays a pivotal role in radioresistance. Unraveling the mechanisms of tumor cell repopulation after radiotherapy is crucial for overcoming radioresistance in gastric cancer.

Materials/Methods: We investigate the interaction between tumor cells and surrounding macrophages, specifically focusing on the activation of NLRP3 expression and inflammasome assembly following irradiation. Utilizing qRT-PCR, western blotting, Chromatin immunoprecipitation, Dual-Luciferase Assay, in vitro co-culture systems, and in vivo subcutaneous tumor models, we elucidate key pathways driving this process.

Results: Our findings show that radiotherapy enhances the binding of the transcription factor Sp1 to the NLRP3 promoter regions, thereby upregulating its transcriptional. Furthermore, irradiation activates the NLRP3 inflammasome, leading to the maturation and secretion of pro-inflammatory cytokines IL-1ß and IL-18. These events contribute to the repopulation of residual gastric cancer cells and drive radioresistance. NLRP3 knockout or mithramycin A (MMA), a specific Sp1 family inhibitor, significantly inhibits tumor growth in co-implanted subcutaneous tumor models containing gastric tumor cells and macrophages following radiation treatment. Targeted modulation of the “Sp1-NLRP3 inflammasome-IL-1ß/IL-18” signaling axis effectively reverses the repopulation of residual tumor cells.

Conclusion: This study reveals a novel mechanism through which the NLRP3 inflammasome mediates the repopulation of residual gastric cancer cells after radiotherapy, providing theoretical insights for improving the radiosensitivity of gastric cancer.