Inflammasome-autophagy crosstalk in the tumor microenvironment.

Abstract

The NLRP3 inflammasome has emerged as a critical sensor of cellular stress within the tumor microenvironment (TME), where its context-dependent activation can exert paradoxical effects on tumor progression and antitumor immunity. Diverse tumor-associated stressors, including mitochondrial dysfunction, reactive oxygen species (ROS), mitochondrial DNA (mtDNA) release, and cGAS-STING signaling, converge on NLRP3 activation, promoting caspase-1-dependent cytokine maturation and gasdermin D (GSDMD)-mediated pyroptosis. However, persistent or dysregulated inflammasome signaling may instead establish an immunosuppressive TME by modulating myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and immune checkpoint responses, thereby facilitating tumor immune escape and progression. A key emerging dimension of this regulatory network is the bidirectional crosstalk between NLRP3 signaling and autophagy, particularly mitochondria-selective mitophagy. Autophagic clearance of damaged mitochondria can restrain inflammasome activation by limiting mitochondrial danger signals, whereas inflammasome-driven inflammatory and metabolic remodeling can reciprocally reshape autophagic responses. This review integrates these traditionally studied pathways into a unified NLRP3-autophagy-mitochondrial stress axis and examines how its stage-, cell-, and context-dependent regulation determines tumor fate. We further critically evaluate pharmacological modulators targeting NLRP3 and autophagy, highlighting opportunities for dual-targeting strategies to simultaneously modulate tumor-intrinsic stress responses and tumor-extrinsic immunity. Overall, defining this mechanistic interface may uncover actionable vulnerabilities and provide a framework for developing context-specific combination therapies that enhance anticancer efficacy.