Extracellular-vesicle-mediated NLRP3 signaling in cancer.

The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has recently been characterized as a major player in cancer-related inflammation, tumor progression, immune modulation, and metastasis. The role of extracellular vesicles (EVs), such as exosomes and microvesicles, as active carriers of NLRP3 signaling components is increasingly being recognized, as they modulate the tumor microenvironment as well as distant tissues primed for metastasis. This study will address the diverse roles of EV-mediated NLRP3 signaling in cancer immunopathogenesis, with a particular emphasis on its role in establishing a pre-metastatic niche and immune evasion. Tumor-derived EVs that include NLRP3 as cargo can reprogram stroma and immune cells at secondary sites in the body to support a metabolic role associated with metastatic colonization. While tumor-derived EVs promote extracellular matrix remodeling, angiogenesis, and the recruitment of immune-suppressive cells, this cascade of processes permits the development of a permissive niche for metastatic colonization, and simultaneously impairs anti-tumor immune surveillance. The provided EV-mediated crosstalk also enables tumor cells to evade immune detection through the downregulation of antigen-presenting cells and the activation of immune-suppressive pathways via NLRP3-dependent mechanisms. The molecular mechanisms underlying EV-driven inflammasome signaling could pave the way for the identification of a novel and specific biomarker, in which its modulation could potentially affect the immune system in the tumor microenvironment (TME) and participate in cancer immunopathogenesis. This review highlights the need to dissect further the interactions and context-specific roles of EV-NLRP3 across cancers to identify new therapeutic strategies for preventing metastasis and enhancing immune therapies.