NLRP3/IL-1 induced myeloid-derived suppressor cells recruitment and PD-L1 upregulation promotes oxaliplatin resistance of hepatocellular carcinoma

Oxaliplatin is commonly used as the first-line chemotherapeutic agent for advanced hepatocellular carcinoma (HCC). Unfortunately, the acquired resistance, limits the effectiveness of oxaliplatin and the underlying mechanisms remain unknown. Therefore, we explored the role of NOD-like receptor protein 3 (NLRP3)/IL-1 beta in mediating oxaliplatin resistance in HCC. We observed that NLRP3/IL-1 beta expression was much higher in oxaliplatin-resistant HCC cells. To further understand its impact on drug resistance, we knocked down NLRP3 and observed that it sensitized HCC cells to the growth-inhibitory effects of oxaliplatin and induced cell apoptosis. NLRP3/IL-1 beta overexpressing tumor cells also attracted polymorphonuclear myeloid-derived suppressor cells. Using mouse models, we demonstrated that NLRP3/IL-1 beta inhibition by short hairpin RNA or MCC950 effectively overcame oxaliplatin resistance. Furthermore, NLRP3/IL-1 beta inhibition resulted in reduced expression of PD-L1. We also found that PD-L1 antibody combined with NLRP3/IL-1 beta blockade displayed significant antitumor effect in HCC. Overall, our study provides compelling evidence supporting the essential role of NLRP3/IL-1 beta in conferring resistance to oxaliplatin and reshaping the immunosuppressive microenvironment in HCC. Targeting NLRP3/IL-1 beta presents a potential therapeutic target for overcoming oxaliplatin resistance and reshaping microenvironment of HCC.