Unlocking inflammatory vulnerabilities: Resistance intervention potential of NLRP3-agonistic pyroptosis

Multidrug resistance (MDR) represents a persistent barrier to effective cancer therapy. We report the discovery of compound 18 , a small-molecule agonist with a distinct structural scaffold that selectively induces pyroptosis in drug-resistant tumor cells, establishing a tumor-selective strategy to bypass MDR. Mechanistically, compound 18 acts as a dual-function modulator: it is predicted to associate with the NLRP3 NACHT domain near the MCC950 pocket, and it effectively amplifies mitochondrial ROS production. This concerted action enhances NLRP3 availability and effectively lowers the activation threshold, driving ASC oligomerization and the execution of pyroptosis via GSDMD cleavage. Crucially, by exploiting the elevated basal stress of malignant cells, compound 18 mediates selective pyroptosis in resistant tumors without inducing broad inflammatory cytokines or toxicity in normal macrophages, indicating a favorable therapeutic window. In models of osimertinib-resistant lung adenocarcinoma, compound 18 restored sensitivity to targeted therapy. This combination drives profound tumor regression, remodels the tumor stroma, and enhances immune cell infiltration, changes associated with productive antitumor immunity. Our findings demonstrate that targeted modulation of the NLRP3 pyroptosis threshold offers a viable strategy to overcome MDR, selectively eliminating resistant tumors without compromising healthy tissue integrity.