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Tumor NLRP3 Amplification Promotes Immunotherapy Resistance by Suppressing MHC Class I Expression
Medrxiv : the Preprint Server for Health Sciences
|November 24, 2025
Summary
The NLRP3 inflammasome pathway drives immunotherapy resistance by suppressing MHC class I expression. Inhibiting NLRP3 restores anti-tumor immunity and overcomes resistance in preclinical cancer models.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immunotherapy resistance is a significant hurdle in cancer treatment.
- The NLRP3 inflammasome pathway has been implicated in adaptive immunotherapy resistance.
- Tumor-intrinsic NLRP3 signaling promotes the recruitment of immunosuppressive cells.
Purpose of the Study:
- To investigate the role of tumor NLRP3 inflammasome signaling in immunotherapy resistance.
- To explore NLRP3 as a potential therapeutic target and biomarker for overcoming resistance.
- To elucidate the molecular mechanisms by which NLRP3 impacts anti-tumor immunity.
Main Methods:
- Correlation analysis of NLRP3 signaling activity with clinical outcomes in melanoma and gastroesophageal adenocarcinoma patients.
- In situ hybridization and spatial transcriptomic analysis to assess NLRP3 expression and signaling.
- Pre-clinical studies using melanoma and GE adenocarcinoma models.
- Signaling pathway analysis using tandem mass spectrometry.
- Orthotopic models to evaluate therapeutic interventions.
Main Results:
- Elevated tumor NLRP3 signaling activity correlates with checkpoint inhibitor resistance in melanoma and GE adenocarcinoma.
- NLRP3 copy-number gain is associated with enhanced NLRP3 signaling in resistant tumors.
- NLRP3 signaling inversely correlates with NLRC5 and MHC class I expression.
- NLRP3 amplification suppresses NLRC5-mediated MHC class I upregulation.
- NLRP3 binds to and inhibits STAT1, thereby suppressing NLRC5 transcription.
- NLRP3 inhibition augments STAT1-NLRC5 signaling and overcomes anti-PD-1 resistance.
Conclusions:
- The tumor NLRP3 inflammasome pathway is a key driver of immunotherapy resistance.
- Targeting NLRP3 can restore anti-tumor immunity by upregulating MHC class I expression.
- NLRP3 inhibition represents a promising strategy to overcome checkpoint inhibitor resistance.
- NLRP3 and related pathways may serve as valuable biomarkers for predicting treatment response.
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