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

Indeed, pre-clinical models of melanoma and GE adenocarcinoma demonstrate that Nlrp3 amplification suppresses NLRC5-mediated MHC class I upregulation, while pharmacologic NLRP3 inhibition augments tumor MHC class I surface levels. Upon activation, mechanistic studies reveal that NLRP3 binds to and inhibits STAT1 dimerization, nuclear translocation, and NLRC5 transcription. Consistent with these findings, inhibiting the NLRP3 inflammasome augments tumor STAT1-NLRC5 signaling, MHC class I surface expression, and overcomes anti-PD-1 resistance in an orthotopic model of microsatellite stable chromosomal instability (CIN) gastric adenocarcinoma.

This work reveals a fundamental link between cellular stress and tumor-mediated immune evasion. In addition, these findings indicate that the tumor NLRP3 inflammasome signaling pathway merits further clinical study as a therapeutic target and a source of companion biomarkers for overcoming checkpoint inhibitor resistance in cancer patients.