Plumbagin remodels the tumor immune microenvironment to overcome cisplatin resistance in tongue squamous cell carcinoma via KLF2 activation and ZWINT/NF-κB inhibition.

Tongue squamous cell carcinoma (TSCC) is a therapeutic challenge due to frequent cisplatin resistance and an immunosuppressive tumor immune microenvironment (TIME). Effective strategies must address both barriers. We evaluated the antitumor effects of plumbagin (PLB) in cisplatin-sensitive and -resistant TSCC cells, as well as in xenograft, patient-derived xenograft, and humanized mouse models. PLB downregulated ZWINT and inhibited NF-κB signaling, thereby restoring cisplatin sensitivity in resistant cells. In vivo, PLB significantly suppressed tumor growth and enhanced cisplatin efficacy. Mechanistically, PLB stabilized KLF2, promoting JAK1/STAT2 signaling, TIME remodeling, and partial restoration of CD8+ T-cell function. These dual actions-tumor chemosensitization via ZWINT/NF-κB inhibition and immune reprogramming via KLF2 activation-were functionally interconnected, as cytokines released by PLB-primed T cells reinforced NF-κB suppression in tumor cells. Collectively, our findings identify PLB as a low-cost small molecule that integrates cisplatin sensitization with immune activation, offering a promising adjunctive strategy for cisplatin-refractory TSCC.