期刊
EMBO JOURNAL
卷 40, 期 7, 页码 -出版社
WILEY
DOI: 10.15252/embj.2020106065
关键词
5‐ FU resistance; Dacarbazine; Ifnb; Mb21d1; Tmem173
资金
- DoD [W81XWH-17-1-0306]
- NIH [R01CA237586, P50CA121974]
- NIDDK
5-FU reduces tumor burden by triggering anti-tumor immunity through activating cancer-cell-intrinsic STING, which requires the involvement of cGAS and interferons. The presence of T cells is also crucial for the efficacy of 5-FU treatment.
5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug, but the mechanisms underlying 5-FU efficacy in immunocompetent hosts in vivo remain largely elusive. Through modeling 5-FU response of murine colon and melanoma tumors, we report that effective reduction of tumor burden by 5-FU is dependent on anti-tumor immunity triggered by the activation of cancer-cell-intrinsic STING. While the loss of STING does not induce 5-FU resistance in vitro, effective 5-FU responsiveness in vivo requires cancer-cell-intrinsic cGAS, STING, and subsequent type I interferon (IFN) production, as well as IFN-sensing by bone-marrow-derived cells. In the absence of cancer-cell-intrinsic STING, a much higher dose of 5-FU is needed to reduce tumor burden. 5-FU treatment leads to increased intratumoral T cells, and T-cell depletion significantly reduces the efficacy of 5-FU in vivo. In human colorectal specimens, higher STING expression is associated with better survival and responsiveness to chemotherapy. Our results support a model in which 5-FU triggers cancer-cell-initiated anti-tumor immunity to reduce tumor burden, and our findings could be harnessed to improve therapeutic effectiveness and toxicity for colon and other cancers.
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