Combinatory Effects of Indoximod and Melatonin Alleviate Myeloid Derived Suppressor Cells Driven Triple Negative Breast Cancer Progression and Metastasis

Triple-negative breast cancer (TNBC) is a distinct molecular subtype of breast cancer, characterized by high mortality and metastasis. Indoleamine 2,3-dioxygenase (IDO) is a highly expressed enzyme in cancer cells that contributes to immunosuppression. The IDO inhibition has been widely used in cancer immunotherapy. In this study, we evaluated the efficacy of indoximod, an IDO inhibitor, in combination with melatonin on TNBC tumor progression and metastasis in vitro and in vivo. Indoximod reduced the viability of 4T1 cells by inducing apoptosis and G2/M cell cycle arrest. Moreover, the combination of melatonin and TNF-α increased indoximod-mediated cell death. In vivo, coadministration of indoximod and melatonin resulted in enhanced antiproliferative and antimetastatic activities in the TNBC model. Tumor generation-induced neutrophil counts, TNF-α, IL-1β, and IL-10 levels were significantly reduced in mice receiving indoximod and melatonin in combination. Importantly, the accumulation of myeloid-derived suppressor cells (MDSCs), a key driver of tumor progression and metastasis, decreased in the primary tumor, metastatic liver, and lung of mice treated with indoximod and melatonin combination. Our findings revealed that melatonin enhances the immunotherapeutic efficacy of indoximod in TNBC.