Abstract 4527: Melatonin as a therapeutic agent for triple-negative breast cancer: Suppressing tumor malignancy and modulating immunity via the FAK pathway

Abstract Background: Triple-negative breast cancer (TNBC) lacks effective targeted therapies and is primarily managed with chemotherapy, which is often limited by toxicity and resistance. Melatonin, an endogenous hormone with anticancer and immunomodulatory properties, has shown promise in various cancers; however, its role in TNBC remains poorly defined. Methods: We investigated the effects of melatonin on human (MDA-MB-231, MDA-MB-468) and murine (4T1) TNBC cells using in vitro assays evaluating proliferation, apoptosis, migration, epithelial-mesenchymal transition (EMT), chemosensitization, and underlying regulatory mechanisms. In vivo efficacy and immune modulation were assessed using a syngeneic orthotopic 4T1 TNBC mouse model. Results: Serum melatonin levels were significantly lower in TNBC patients than in healthy individuals. In vitro, melatonin inhibited TNBC cell viability, motility, and tumorsphere formation while inducing apoptosis. Mechanistically, melatonin downregulated focal adhesion kinase (FAK) and programmed death-ligand 1 (PD-L1) expression; FAK inhibition enhanced melatonin sensitivity, whereas FAK overexpression attenuated its effects. Melatonin also potentiated cisplatin-induced cytotoxicity. In vivo, melatonin suppressed tumor growth, increased CD8+ T cell infiltration, and reduced PD-L1 and FOXP3+ regulatory T cells within the tumor microenvironment. Conclusions: Melatonin exerts antitumor and immunomodulatory effects in TNBC via inhibition of the FAK-PD-L1 signaling axis. These findings support its potential as a safe, accessible adjuvant therapy to improve TNBC treatment outcomes. Citation Format: Chi-Wen Luo, Cheng-Che Wu, Mei-Ren Pan, Chung-Liang Li, Fang-Ming Chen, Ming-Feng Hou. Melatonin as a therapeutic agent for triple-negative breast cancer: Suppressing tumor malignancy and modulating immunity via the FAK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4527.