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Simple Summary: 5-Fluorouracil (5-FU), in combination with various therapeutic agents, is the main strategy for patients with high risk of stage 2, and advanced stages of, human colorectal cancer. Although 5-FU-based chemotherapy causes myeloid cell suppression, which has long been considered as a major adverse effect in certain cancer patients, recent studies determined that 5-FU selectively kills myeloid-derived suppressor cells (MDSCs), to increase cytotoxic T lymphocyte activation. However, the molecular mechanism underlying 5-FU's suppression of MDSCs is incompletely understood. We report here that 5-FU activates p53, to upregulate Fas expression in MDSCs, to increase MDSC sensitivity to FasL-induced apoptosis in vitro. 5-FU therapy upregulates Fas expression, to suppress MDSC accumulation, to increase CTL tumor infiltration in tumor-bearing mice. In human colorectal cancer patients, 5-FU-based chemotherapy suppresses MDSCs and increases CTLs level. Our findings determine that the p53-Fas pathway links 5-FU to MDSC suppression. Myelosuppression is a major adverse effect of 5-fluorouracil (5-FU) chemotherapy. However, recent findings indicate that 5-FU selectively suppresses myeloid-derived suppressor cells (MDSCs), to enhance antitumor immunity in tumor-bearing mice. 5-FU-mediated myelosuppression may thus have a beneficial effect for cancer patients. The molecular mechanism underlying 5-FU's suppression of MDSCs is currently unknown. We aimed at testing the hypothesis that 5-FU suppresses MDSCs through enhancing MDSC sensitivity to Fas-mediated apoptosis. We observed that, although FasL is highly expressed in T cells, Fas is weakly expressed in myeloid cells in human colon carcinoma, indicating that downregulation of Fas is a mechanism underlying myeloid cell survival and accumulation in human colon cancer. 5-FU treatment upregulated expression of both p53 and Fas, and knocking down p53 diminished 5-FU-induced Fas expression in MDSC-like cells, in vitro. 5-FU treatment also increased MDSC-like cell sensitivity to FasL-induced apoptosis in vitro. Furthermore, we determined that 5-FU therapy increased expression of Fas on MDSCs, suppressed MDSC accumulation, and increased CTL tumor infiltration in colon tumor-bearing mice. In human colorectal cancer patients, 5-FU chemotherapy decreased MDSC accumulation and increased CTL level. Our findings determine that 5-FU chemotherapy activates the p53-Fas pathway, to suppress MDSC accumulation, to increase CTL tumor infiltration. [ABSTRACT FROM AUTHOR]