The NLRP3 inflammasome in gynecological cancers: a double-edged sword shaping the immune microenvironment and immunotherapy response

The NLRP3 inflammasome is a multi-protein innate immune complex that functions as a critical sensor of cellular danger signals, yet its role in gynecological malignancies remains incompletely understood. This mini-review systematically evaluates the paradoxical functions of NLRP3 across the three major gynecological cancers-ovarian, endometrial, and cervical-with emphasis on its dual impact on the tumor immune microenvironment and immunotherapy response. In ovarian cancer, NLRP3 drives immune suppression through PD-L1 upregulation and M2 macrophage polarization via the USP19-STAT6 axis, while simultaneously enhancing cisplatin sensitivity through FTO-mediated pyroptotic signaling. In endometrial cancer, the ERRα-NLRP3-GSDMD pathway regulates pyroptosis in a molecular subtype-dependent manner, with pro-immune effects in MSI-H tumors but potentially pro-tumorigenic consequences in microsatellite-stable subtypes. In cervical cancer, HPV oncoproteins employ multiple mechanisms-including Foxm1-mediated transcriptional suppression, KIF23-dependent GSDMD blockade, and non-coding RNA regulation-to silence NLRP3 and evade immune surveillance. Beyond tumor type-specific mechanisms, the tumor-intrinsic PD-L1/NLRP3 axis has been identified as a key driver of resistance to anti-PD-1 immunotherapy across cancers, whereas NLRP3-activating nanovaccines and small-molecule agonists offer strategies to convert immunologically cold tumors into immunoresponsive ones. We further discuss combination approaches integrating NLRP3 modulators with immune checkpoint inhibitors and PARP inhibitors via the cGAS-STING-NLRP3 axis. Understanding the context-dependent functions of NLRP3 is essential for developing precision immunotherapeutic strategies tailored to tumor type, molecular subtype, and immune context in gynecological malignancies.