NLRP3 inflammasome modulates immune evasion and chemotherapy sensitivity in gynecological cancersNew research identifies a key driver in gynecological cancer cells

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.