Melatonin-mediated cGAS-STING signal in senescent macrophages promote TNBC chemotherapy resistance and drive the SASP.

The build-up of senescent cells in tissues is a key indicator of aging, associated with negative prognosis and therapy resistance. Despite immune dysfunction related to aging, also known as immunosenescence, is recognized as a factor in this process, the exact mechanisms are still unclear. In this study, we reported that melatonin deficiency accelerated macrophage senescence in triple-negative breast cancer, whereas melatonin could defend macrophages against senescence through the Nfatc1-Trim26-cgas-Sting pathway. Mechanistically, melatonin enhanced the nuclear translocation of Nfatc1 and elevated Trim26 transcription levels. Trim26, functioning as an E3 ligase, ubiquitinates cgas, thereby inhibiting the activation of the cgas-Sing pathway and consequently preventing cell senescence. Conversely, melatonin deficiency induced cgas-Sting pathway activation to promote macrophage aging. Our results show that melatonin inhibited macrophage senescence and improved chemotherapy responsiveness, with further enhancement when combined with the cgas inhibitor (G150). Overall, our findings indicated that melatonin protects macrophages from immunosenescence, suggesting its therapeutic potential for enhancing chemotherapy response.