NLRP3 inflammasome acts as a double-edged sword in gynecological cancers, influencing immune microenvironment and immunotherapy response.

The NLRP3 inflammasome is a crucial multi-protein innate immune complex that senses cellular danger signals, orchestrating inflammatory and immune responses. While essential for host defense, its dysregulation contributes to chronic inflammation and various diseases, including cancer. In gynecological malignancies, the precise, context-dependent functions of NLRP3 remain incompletely understood, presenting a significant gap in developing targeted immunotherapies. Current standard-of-care treatments often face challenges like immune evasion and resistance, highlighting the need to explore novel pathways like NLRP3 for therapeutic intervention.

This mini-review systematically evaluated the paradoxical functions of the NLRP3 inflammasome across the three major gynecological cancers: ovarian, endometrial, and cervical. The authors synthesized findings from various preclinical and clinical studies, focusing on NLRP3's dual impact on the tumor immune microenvironment and response to immunotherapy. They explored tumor-type-specific mechanisms, the role of the PD-L1/NLRP3 axis in immunotherapy resistance, and potential therapeutic strategies involving NLRP3 modulation, including nanovaccines and small-molecule agonists.

The review revealed that the NLRP3 inflammasome plays complex, often opposing roles depending on the cancer type and molecular context. In ovarian cancer, NLRP3 drives immune suppression via PD-L1 upregulation and M2 macrophage polarization through the USP19-STAT6 axis. Simultaneously, it enhances cisplatin sensitivity by FTO-mediated pyroptotic signaling. In endometrial cancer, the ERRα-NLRP3-GSDMD pathway regulates pyroptosis in a molecular subtype-dependent manner, showing pro-immune effects in MSI-H tumors but potentially pro-tumorigenic consequences in microsatellite-stable (MSS) subtypes. In cervical cancer, HPV oncoproteins actively silence NLRP3 and evade immune surveillance through multiple mechanisms, including Foxm1-mediated transcriptional suppression, KIF23-dependent GSDMD blockade, and non-coding RNA regulation. > The tumor-intrinsic PD-L1/NLRP3 axis was identified as a key driver of resistance to anti-PD-1 immunotherapy across various cancers, highlighting a critical mechanism of immune evasion. Furthermore, NLRP3-activating nanovaccines and small-molecule agonists offer promising strategies to convert immunologically 'cold' tumors into immunoresponsive ones, potentially broadening the efficacy of existing immunotherapies.