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Tumor NLRP3 Amplification Promotes Immunotherapy Resistance by Inhibiting STAT1 Signaling and MHC Class I Expression
Balamayroon Theivanthiran1, Nagendra Yarla2, Kaylee Villarreal2
1Lineberger Comprehensive Cancer Center Department of Medicine, Division of , University of North Carolina, Chapel Hill, United States of America.
The Journal of Clinical Investigation
|August 13, 2026
Summary
Elevated tumor NLRP3 inflammasome signaling drives immunotherapy resistance by suppressing MHC class I expression. Inhibiting NLRP3 overcomes resistance, suggesting it as a therapeutic target and biomarker for cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immunotherapy resistance is a major challenge in cancer treatment.
- Predictive biomarkers are crucial for selecting effective combination immunotherapies.
Purpose of the Study:
- To investigate the role of tumor-intrinsic NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling in immunotherapy resistance.
- To identify NLRP3 as a potential therapeutic target and predictive biomarker.
Main Methods:
- Analysis of clinical cohorts (melanoma, gastroesophageal adenocarcinoma) for NLRP3 signaling and copy-number gain.
- In situ hybridization and spatial transcriptomic analysis.
- Mechanistic studies involving STAT1, NLRC5, and MHC class I expression.
- Pharmacologic inhibition of NLRP3 in an orthotopic gastric cancer model.
Main Results:
- Elevated tumor NLRP3 signaling correlates with checkpoint inhibitor resistance.
- NLRP3 copy-number gain is observed in resistant tumors.
- NLRP3 suppresses NLRC5-mediated MHC class I upregulation by inhibiting STAT1.
- NLRP3 inhibition restores STAT1-NLRC5 signaling, enhances MHC class I expression, and overcomes anti-PD-1 resistance in vivo.
Conclusions:
- Tumor-intrinsic NLRP3 inflammasome signaling is a key mechanism of immune evasion and immunotherapy resistance.
- Targeting the NLRP3 pathway can overcome resistance to immune checkpoint inhibitors.
- NLRP3 serves as a potential therapeutic target and companion biomarker for guiding cancer immunotherapy.
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