Reversing chemoresistance in ovarian cancer: network pharmacology reveals how hydroxychloroquine/sulfasalazine duotherapy remodels tumor inflammatory–immune microenvironment

Introduction Chemoresistance is a key contributor of ovarian cancer (OC) mortality. Clinical observations of extended survival in OC patients with rheumatic comorbidities following anti-rheumatic treatment suggest hydroxychloroquine (HCQ) and sulfasalazine (SSZ) could act as chemosensitizers. However, how the HCQ/SSZ combination counteracts platinum–taxane resistance remains unclear. Methods A multiomics strategy was applied, integrating transcriptomics from resistant and sensitive OC models with network pharmacology, consensus clustering, machine learning, and molecular docking, which indicated potential binding to predicted targets (e.g., SSZ–tumor necrosis factor (TNF): −6.99 kcal/mol). Validation included in vitro drug sensitivity assays and clinical cytokine profiling. Results Analysis identified 26 overlapping genes as shared targets and classified patients into chemoresistant (Subtype 1) and chemosensitive (Subtype 2) subgroups, with Subtype 1 associated with protumorigenic pathway enrichment, immunosuppressive features, and poorer prognosis. A seven-hub-gene predictive signature was established. HCQ/SSZ appeared to remodel the inflammatory–immune tumor microenvironment, primarily through cytokine and nuclear factor kappa B (NF-κB) signaling. Clinical cytokine data supported a localized immunosuppressive niche, and in vitro evidence confirmed cytotoxic effects. Patients receiving long-term HCQ/SSZ therapy generally showed improved clinical outcomes. Conclusion This study suggests that HCQ/SSZ may reverse chemoresistance by reprogramming the inflammatory–immune microenvironment, offering a molecular rationale for further investigation into their repurposing as chemosensitizers and maintenance therapies in OC.