Fusobacterium nucleatum (Fn) is a tumor-associated obligate anaerobic bacterium, which has a role in the progression of colorectal cancer (CRC). Fn can invade and promote colon epithelial cells proliferation. However, how Fn survives and proliferates in its host cells remains largely unknown. In this study, we aimed to determine the molecular mechanisms underlying the morphology, survival, and proliferation of Fn in THP-1-derived macrophages (dTHP1). For the first time, we found that Fn is a facultative intracellular bacterium that can survive and limited proliferate in dTHP1 cells up to 72 h, and a live Fn infection can inhibit apoptosis of dTHP1 cells by activating the PI3K and ERK pathways. Both Fn bacteria and dTHP1 cells exhibit obvious morphological changes during infection. In addition, Infection of Fn-induced indoleamine 2,3-dioxygenase (IDO) expression by TNF-α-dependent and LPS-dependent pathway in a time-dependent and dose-dependent manner, and the IDO-induced low tryptophan and high kynurenine environment inhibited the intracellular multiplication of Fn in dTHP1 cells. IDO expression further impaired the function of peripheral blood lymphocytes, permitting the escape of Fn-infected macrophages from cell death. IDO inhibition abrogated this effect caused by Fn and relieved immune suppression. In conclusion, we identified IDO as an important player mediating intracellular Fn proliferation in macrophages, and inhibition of IDO may aggravate infection in Fn-associated tumor immunotherapy.