Targeting Inflammasomes to Combat Cisplatin Resistance in Ovarian Cancer

NLRP3 inflammasome activation drives cisplatin resistance in ovarian cancer, positioning inflammasome blockade as a strategy to restore platinum sensitivity.

In vitro cisplatin exposure markedly increased caspase‑1 activity, IL‑1β secretion, membrane pore formation, and markers of lytic cell death across ovarian cancer models. Resistant lines showed higher IC50 values; mechanistic data implicate NLRP3 as central to this stress‑inflammatory response.

Elevated inflammasome activation implicates both NLRP3 and related sensors in caspase‑1–dependent cytokine maturation, gasdermin‑mediated pore formation and pyroptotic lytic death. These pathways intersect DNA‑damage response mechanisms that influence cell fate after platinum lesions.

Cell‑line studies show heterogeneity in inflammasome engagement and cisplatin sensitivity: A2780 remained cisplatin‑sensitive (IC50 ≈10.4 µM), while ACRP (acquired resistance, IC50 ≈35.9 µM) and OVCAR3 (innate resistance, IC50 ≈43.5 µM) exhibited greater caspase‑1 activity, cytokine output and pore formation—indicating biomarker selection must account for cell‑context differences.

Preclinical strategies should prioritize combining selective inflammasome pathway inhibitors (for example, caspase‑1 inhibitors or NLRP3 blockers) with cisplatin; testing for synergy with DNA‑damage response modulators such as PARP inhibitors or employing agents that restore apoptotic/pyroptotic balance (for instance, GSDME re‑expression) are logical next steps. Early functional endpoints—viability, IC50 shifts, cytokine profiles and migration assays—should identify combinations that reverse resistance signals and reduce invasive behavior.

These findings support prioritized translational testing of inflammasome‑directed combinations to overcome platinum resistance.

Key Takeaways:

• Inflammasome activation (notably NLRP3) is linked to cisplatin resistance in ovarian cancer models.
• Patients with platinum‑resistant epithelial ovarian cancer and translational preclinical cohorts.
• Prioritize preclinical combinations of inflammasome inhibitors with DNA‑damage modulators and biomarker development.