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Adv."],"published-print":{"date-parts":[[2026,5,22]]},"abstract":"<jats:p>\n                    Colorectal cancer (CRC) commonly metastasizes to the liver (CRLM), where it is the leading cause of CRC-related deaths. While immune checkpoint therapies show promise, their effectiveness is limited in CRLM due to the immunosuppressive liver tumor microenvironment (TME). Using multiregional tissue sampling from CRLM patient samples, we identified distinct immune zones within CRLM. Active Granzyme\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells were found in normal liver tissue, while CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in the tumor core were dysfunctional. At the tumor margin, we observed a pre-exhausted immune zone enriched in\n                    <jats:italic toggle=\"yes\">\n                      THBS1\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    monocytes and CD47\n                    <jats:italic toggle=\"yes\">\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    CD8\n                    <jats:italic toggle=\"yes\">\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    T cells. Trajectory analysis showed that\n                    <jats:italic toggle=\"yes\">\n                      THBS1\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    monocytes differentiate into\n                    <jats:italic toggle=\"yes\">\n                      SPP1\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    macrophages, which accumulate in the tumor core and promote immune suppression via\n                    <jats:italic toggle=\"yes\">TIM-3<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">CTLA-4<\/jats:italic>\n                    on exhausted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. The presence of\n                    <jats:italic toggle=\"yes\">\n                      SPP1\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    macrophages correlates with increased T cell exhaustion and poor survival, suggesting them as potential targets to restore antitumor immunity in CRLM.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aed1296","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T17:58:41Z","timestamp":1779472721000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Multiregional profiling reveals\n                    <i>THBS1<\/i>\n                    -\n                    <i>SPP1<\/i>\n                    monocyte-macrophage axis drives immunosuppression and outcome in colorectal liver metastases"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9153-7432","authenticated-orcid":true,"given":"Gaia","family":"Bellomo","sequence":"first","affiliation":[{"name":"Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9003-4794","authenticated-orcid":true,"given":"Jayden","family":"Gittens","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Brunning","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7790-7490","authenticated-orcid":true,"given":"Maidinaimu","family":"Abudula","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5608-001X","authenticated-orcid":true,"given":"Robert P.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3445-0013","authenticated-orcid":true,"given":"Michael C.","family":"Schmid","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4159-5931","authenticated-orcid":true,"given":"Ainhoa","family":"Mielgo","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, 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