%0 Journal Article
%T 5-Fluorouracil efficacy requires anti-tumor immunity triggered by cancer-cell-intrinsic STING.
%A Tian J
%A Zhang D
%A Kurbatov V
%A Wang Q
%A Wang Y
%A Fang D
%A Wu L
%A Bosenberg M
%A Muzumdar MD
%A Khan S
%A Lu Q
%A Yan Q
%A Lu J
%J EMBO J
%V 40
%N 7
%D 04 2021 1
%M 33615517
%F 14.012
%R 10.15252/embj.2020106065
%X 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.