Objective:

To systematically evaluate the paradoxical functions of NLRP3 in ovarian, endometrial, and cervical cancers, emphasizing its dual impact on the tumor immune microenvironment and responses to immunotherapy.

Approach:

• Ovarian Cancer: NLRP3 drives immune suppression through PD-L1 upregulation and M2 macrophage polarization via the USP19-STAT6 axis, while enhancing cisplatin sensitivity through FTO-mediated pyroptotic signaling.
• Endometrial Cancer: The ERRα-NLRP3-GSDMD pathway regulates pyroptosis in a molecular subtype-dependent manner, with pro-immune effects in MSI-H tumors and potentially pro-tumorigenic effects in microsatellite-stable subtypes.
• Cervical Cancer: HPV oncoproteins silence NLRP3 through multiple mechanisms, including Foxm1-mediated transcriptional suppression, KIF23-dependent GSDMD blockade, and non-coding RNA regulation, to evade immune surveillance.
• Immunotherapy Resistance: The tumor-intrinsic PD-L1/NLRP3 axis is a key driver of resistance to anti-PD-1 immunotherapy across cancers.
• Therapeutic Strategies: NLRP3-activating nanovaccines and small-molecule agonists are proposed to convert immunologically cold tumors into immunoresponsive ones.
• Combination Approaches: Integration of NLRP3 modulators with immune checkpoint inhibitors and PARP inhibitors via the cGAS-STING-NLRP3 axis is discussed.

Key Findings:

• NLRP3 has dual roles in gynecological cancers, promoting both immune suppression and anti-tumor immunity.
• In ovarian cancer, NLRP3 contributes to immune suppression and enhances sensitivity to chemotherapy.
• In endometrial cancer, NLRP3's effects vary by molecular subtype, influencing tumor behavior.
• In cervical cancer, HPV manipulates NLRP3 to evade immune detection.
• The PD-L1/NLRP3 axis is implicated in resistance to immunotherapy.

Interpretation:

Understanding the context-dependent functions of NLRP3 is essential for developing tailored immunotherapeutic strategies in gynecological malignancies.

Limitations:

• The complexity of the immune microenvironment in gynecological cancers complicates the interpretation of NLRP3's role.
• The review does not provide clinical trial data or specific patient outcomes related to NLRP3 modulation.

Conclusion:

A nuanced understanding of NLRP3's role in gynecological cancers is essential for advancing precision immunotherapy.