Melatonin inhibits FAK signaling to suppress PD-L1 expression and enhance chemosensitivity in triple-negative breast cancer

TL;DR

Melatonin may help treat triple-negative breast cancer by reducing tumor growth and improving immune response through a specific signaling pathway.

Contribution

This study reveals melatonin's novel role in suppressing TNBC via FAK-PD-L1 signaling and enhancing chemosensitivity.

Findings

TNBC patients had lower serum melatonin levels compared to healthy controls.

Melatonin inhibited tumor cell viability, migration, and PD-L1 expression via FAK signaling.

Melatonin enhanced chemotherapy effectiveness and increased anti-tumor immune cell infiltration in mice.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targetable hormone receptors, making conventional chemotherapy the primary treatment option, despite its associated toxicity and potential for drug resistance. Melatonin, a natural hormone with anticancer and immunomodulatory properties, has shown promise in multiple cancers; however, its role in TNBC remains unclear.

We analyzed serum melatonin levels in TNBC patients and healthy controls. The biological effects of melatonin were then evaluated in human (MDA-MB-231, MDA-MB-468) and murine (4T1) TNBC cell lines. In vitro assays assessed proliferation, apoptosis, migration, epithelial-mesenchymal transition (EMT), and chemosensitization. Mechanistic pathways were analyzed, and an orthotopic 4T1 syngeneic mouse model was employed to confirm antitumor and immunomodulatory effects in vivo.

We found that TNBC patients had significantly lower serum melatonin levels than healthy controls. In vitro, melatonin reduced cell viability, migration, and tumorsphere formation, and promoted apoptosis. Mechanistically, it downregulated focal adhesion kinase (FAK) and programmed death-ligand 1 (PD-L1). FAK inhibition increased melatonin sensitivity, whereas FAK overexpression conferred resistance. Melatonin also enhanced cisplatin cytotoxicity. In vivo, melatonin treatment suppressed tumor growth, increased CD8⁺ T-cell infiltration, and decreased PD-L1 expression and the number of FOXP3⁺ regulatory T cells in the tumor microenvironment.

Melatonin suppresses TNBC progression by inhibiting proliferation and migration and by modulating the immune microenvironment through the FAK-PD-L1 axis. These findings highlight melatonin as a potential low-toxicity adjunct to enhance the efficacy of current TNBC therapies.

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