NLRP3 inflammasome as a therapeutic target in oral squamous cell carcinoma: implications for tumorigenesis and immunomodulation.

Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy strongly influenced by chronic inflammation. Central to this process is the NLRP3 inflammasome, a cytosolic multiprotein complex that senses cellular stress and mediates the maturation of pro-inflammatory cytokines such as IL-1β and IL-18. Recent studies highlight NLRP3's dual role in OSCC pathogenesis, contributing to tumor progression, immune evasion, and therapy resistance, while also possessing potential tumor-suppressive capabilities via pyroptosis induction. NLRP3 activation promotes epithelial-mesenchymal transition, lymphangiogenesis, and chemoresistance through signaling networks involving SOAT1, miR-22, and PRDX1. Additionally, it regulates the tumor immune microenvironment by modulating tumor-associated macrophages, neutrophils, and cytokines like IL-6 and IL-1β. Oral pathogens further shape this landscape by influencing NLRP3 activity, linking the microbiome to carcinogenesis. Despite its protumoral functions, NLRP3 can stimulate anti-tumor immunity under certain conditions, making it a complex therapeutic target. Emerging strategies to modulate NLRP3 include small-molecule inhibitors (e.g., MCC950, BAY-117082), plant-derived compounds (e.g., oridonin, Bacopa monnieri), and immunotherapy approaches, including intratumoral NLRP3 agonists combined with checkpoint blockade. This review synthesizes the multifaceted roles of NLRP3 in OSCC, highlighting its centrality in inflammation-driven tumor biology and its promise as a therapeutic target. Understanding the contextual duality of NLRP3 activation is critical for developing precision therapies that disrupt its tumor-supportive effects while preserving or enhancing its immunogenic functions.