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ATR inhibitors (ATRi) have been proven to cooperate with radiation to promote antitumor immunity, but it is unclear whether ATRi could facilitate the efficacy of IR and ICI combinations in CRCs. This study aimed to investigate the efficacy of combining ATRi, irradiation (IR), and anti\u2010PD\u2010L1 antibodies in CRC mouse models with different microsatellite statuses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">The efficacy of combining ATRi, IR, and anti\u2010PD\u2010L1 antibodies was evaluated in CRC tumors. The tumor microenvironment and transcriptome signatures were investigated under different treatment regimens. The mechanisms were explored via cell viability assay, flow cytometry, immunofluorescence, immunoblotting, co\u2010immunoprecipitation, and real\u2010time quantitative PCR in multiple murine and human CRC cell lines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Combining ATRi berzosertib and IR enhanced CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration and enhanced the efficacy of anti\u2010PD\u2010L1 therapy in mouse CRC models with different microsatellite statuses. The mechanistic study demonstrated that IR + ATRi could activate both the canonical cGAS\u2010STING\u2010pTBK1\/pIRF3 axis by increasing cytosolic double\u2010stranded DNA levels and the non\u2010canonical STING signaling by attenuating SHP1\u2010mediated inhibition of the TRAF6\u2010STING\u2010p65 axis, via promoting SUMOylation of SHP1 at lysine 127. By boosting the STING signaling, IR + ATRi induced type I interferon\u2010related gene expression and strong innate immune activation and reinvigorated the cold tumor microenvironment, thus facilitating immunotherapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">The combination of ATRi and IR could facilitate anti\u2010PD\u2010L1 therapy by promoting STING signaling in CRC models with different microsatellite statuses. The new combination strategy raised by our study is worth investigating in the management of CRC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.12412","type":"journal-article","created":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T02:59:49Z","timestamp":1677639589000},"page":"435-454","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":83,"title":["Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer"],"prefix":"10.34133","volume":"43","author":[{"given":"Chaofan","family":"Liu","sequence":"first","affiliation":[{"name":"Huazhong University of Science and Technology","place":["Wuhan, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Wang","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology","place":["Wuhan, P. R. 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