5‐Fluorouracil efficacy requires anti‐tumor immunity triggered by cancer‐cell‐intrinsic STING

Abstract

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.

Thermosensitive Interfacial Migration of 5-FU in the Microenvironment of Pluronic Block Copolymers

“…However, 5-FU has a chemical structure similar to uracil and thymine and interferes with nucleotide synthesis and incorporates into DNA, which may have a mutational impact on both surviving tumor and healthy cells [ 2 ]. Additionally, 5-FU could trigger cancer cell-initiated anti-tumor immunity to reduce the tumor burden, and to improve therapeutic effectiveness for colon and other cancers [ 3 ]. Despite these advances, drug resistance remains a significant limitation to the clinical use of 5-FU [ 4 ].…”

Metabolism and Innate Immunity Meet at the Mitochondria

“…Depletion of cellular pyrimidines via genetic intervention or treatment with the pyrimidine nucleoside analogue 5-fluorouracil (5-FU) triggered mtDNA-dependent cGAS-STING activation, demonstrating that this mtDNA release pathway may be of relevance in a number of clinical contexts ( Sprenger et al, 2021 ). For instance, cGAS-STING dependent type I IFN production is triggered by 5-FU in cancer cells and supports effective anti-tumour immunity in colorectal cancer ( Tian et al, 2021 ). Intriguingly, YME1L was found to be frequently mutated in colorectal cancer tissue, which may drive the migration of mtDNA to the nucleus observed in these cancers ( Srinivasainagendra et al, 2017 ).…”

cGAS–STING signaling pathway in gastrointestinal inflammatory disease and cancers

“…98,108,117,119 Micronuclei-like DNA structures increased upon 5-FU treatment and the efficacy of 5-FU to reduce tumor burden in murine colorectal cancer models was dependent on STING-mediated anti-tumor immunity. 98 Antilipemic agent lovastatin, served as SHP2 agonist, enhanced the sensitivity of colorectal cancer to DNA damaging drug CPT-11. Exploration of the molecular mechanism indicated that SHP2 inhibited DNA damage repair via dephosphorylating PARP1, thus activating cGAS-STING signaling pathway (Table 3).…”