Pineal melatonin modulates responsiveness to exogenous melatonin via the IFN-γ–CXCL9/10–CXCR3 axis in gastric cancer

Abstract Background Melatonin is a pineal-derived neuroendocrine hormone with pleiotropic actions on tumor biology and immune regulation. Although exogenous melatonin has been reported to exert antitumor and immunomodulatory effects, whether these actions depend on an intact endogenous pineal melatonin background remains unclear. In particular, the role of endogenous melatonin in conditioning chemokine-mediated antitumor effects has not been defined. Methods A male mouse gastric cancer model was used to investigate the interplay between endogenous and exogenous melatonin in tumor growth, immune infiltration, and chemokine signaling. Tumor and immune tissues were analyzed by flow cytometry, immunofluorescence, RT-qPCR and Western blotting. In vitro assays evaluated the direct effects of melatonin on chemokine expression in gastric cancer cells. Results Exogenous melatonin suppressed tumor growth in vivo and inhibited tumor cell proliferation in vitro. These effects were accompanied by increased intratumoral CD8+ T-cell accumulation and activation of the IFN-γ–CXCL9/10–CXCR3 axis within tumor tissues. Pinealectomy alone did not significantly alter baseline tumor progression, but it attenuated the tumor and chemokine responses to exogenous melatonin and disturbed splenic immune homeostasis. In gastric cancer cells, melatonin directly induced CXCL9 and CXCL10 expression, indicating that tumor cells contribute to endocrine-responsive chemokine amplification. Conclusions Endogenous pineal melatonin contributes to optimal responsiveness to exogenous melatonin in this gastric cancer model. It provides a critical endocrine context for effective chemokine-mediated immune modulation by exogenous melatonin. By enhancing intratumoral immune cell recruitment while preserving immune homeostasis, melatonin integrates neuroendocrine and immune regulation to suppress tumor growth.