{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:23:03Z","timestamp":1790760183731,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T00:00:00Z","timestamp":1660176000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["X2YXD2172070"],"award-info":[{"award-number":["X2YXD2172070"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2021A1515012123"],"award-info":[{"award-number":["2021A1515012123"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>The activation of STING (stimulator of interferon genes) pathway enhances antitumor immunity in small\u2010cell lung cancer (SCLC), while the DNA damage induced by non\u2010cGAMP\u2010based agonists is a potent inducer of STING activity. Here, we investigate the intrinsic expression of STING in cancer cells and evaluate the value of the combination of ATR and TOP1 inhibitors in enhancing antitumor immunity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>STING expression was assessed at mRNA and protein levels in SCLC and normal lung tissues. Transcriptomic subsets of SCLC were identified based on STING\u2010related genes. Distinct mutation and immunogenomic profiles of these subsets were determined. The direct antitumor efficacy and the potential of enhancing antitumor immunity of the strategy using the ATR\u2010TOP1\u2010inhibitor combination were tested in SCLC cell lines.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The intrinsic expression of STING was significantly reduced in SCLC compared to normal lung tissues (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Three STING\u2010related SCLC subtypes were identified in which the STING\u2010high subtype was associated with (1) high immune infiltration, (2) high expression of genes related to MHC and immune checkpoints, and (3) high EMT and ferroptosis score. On the contrary, the STING\u2010low subtype was enriched with pathways related to DNA damage response (DDR) and cell cycle progression. The association between the DDR pathway activity and the STING\u2010IFN innate immune response was verified by in vitro experiments in which the inhibition of ATR and TOP1 triggered the expression of genes encoding type I IFN signaling and pro\u2010inflammatory cytokines\/chemokines in a STING\u2010low SCLC cell line.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study verifies that activation of the STING\u2010IFN response by ATR and TOP1 inhibitors might be a therapeutic strategy to improve the response to immune checkpoint therapy in STING\u2010low SCLC. Furthermore, the combinations of ATR and TOP1 inhibitors can augment tumor inflammation in STING\u2010low SCLC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.5109","type":"journal-article","created":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T06:29:48Z","timestamp":1660285788000},"page":"4864-4881","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Immunogenicity of small\u2010cell lung cancer associates with <scp>STING<\/scp> pathway activation and is enhanced by <scp>ATR<\/scp> and <scp>TOP1<\/scp> inhibition"],"prefix":"10.1002","volume":"12","author":[{"given":"Xuetao","family":"Li","sequence":"first","affiliation":[{"name":"The Laboratory of Computational Medicine and Systems Biology, School of Medicine South China University of Technology  Guangzhou Guangdong 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