Plumbagin remodels the tumor immune microenvironment to overcome cisplatin resistance in tongue squamous cell carcinoma.
Plumbagin remodels the tumor immune microenvironment to overcome cisplatin resistance in tongue squamous cell carcinoma via KLF2 activation and ZWINT/NF-κB inhibition.
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Key Findings
Abstract
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 CD8T-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.
Affiliation
Zichen Xu
External References
- PubMed ID:
- 41056769
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