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Tumor NLRP3 Amplification Promotes Immunotherapy Resistance by Inhibiting STAT1 Signaling and MHC Class I Expression

Balamayroon Theivanthiran,¹ Nagendra Yarla,² Kaylee Villarreal,² Y-Van Nguyen,¹ Mahere Rezazade Bazaz,¹ Ernesto Pena Calderin,¹ Linda Cao,¹ Kyra Majors,¹ Michael P. Plebanek,¹ Alisha Holtzhausen,³ Emily Bolch,² Douglas B. Johnson,⁴ Hope Uronis,² John H. Strickler,² Nicholas C. DeVito,² and Brent A. Hanks¹

Published August 13, 2026 - More info

Immunotherapy resistance remains a challenge in immuno-oncology and predictive biomarkers are needed to guide combination immunotherapy selection for the individual patient. We show that elevated tumor-intrinsic NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) signaling activity correlates with checkpoint inhibitor resistance in several independent cohorts of stage III/IV melanoma and gastroesophageal (GE) adenocarcinoma patients. In situ hybridization demonstrates that tumor NLRP3 copy-number gain is observed in immunotherapy resistant melanomas and GE adenocarcinomas harboring enhanced NLRP3 signaling activity. Nlrp3 amplification suppresses NOD-, LRR-, and CARD-containing 5 (NLRC5)-mediated MHC class I upregulation, while spatial transcriptomic analysis of patient-derived GE adenocarcinomas confirms that NLRP3 signaling activity inversely correlates with NLRC5 and major histocompatibility (MHC) class I-associated gene expression. Mechanistically, NLRP3 binds to and inhibits signal transducer and activator of transcription 1 (STAT1) dimerization, nuclear translocation, and NLRC5 transcription. Consistent with these findings, pharmacologic inhibition of the NLRP3 inflammasome augments tumor STAT1-NLRC5 signaling, enhances MHC class I surface expression, and overcomes anti-PD-1 resistance in an orthotopic model of gastric adenocarcinoma. This work reveals a fundamental link between cellular stress and tumor-mediated immune evasion and indicates that the tumor NLRP3 signaling pathway merits further clinical study as a therapeutic target and a source of companion biomarkers for overcoming checkpoint inhibitor resistance in cancer patients.

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