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In this study, we integrated single\u2011cell RNA\u2011sequencing and spatial transcriptomics of patient tumor specimens to dissect the interplay between the hepatic tumor microenvironment and chemotherapy resistance. We identified a specific macrophage subpopulation marked by elevated expression of Secreted Phosphoprotein 1 (\n                    <jats:italic>SPP1<\/jats:italic>\n                    ) that is significantly enriched in insufficient responders to NAC. Mechanistically, these\n                    <jats:italic>SPP1<\/jats:italic>\n                    \u2009+\u2009macrophages exhibit a pro\u2011tumoral transcriptomic profile and directly suppress CD8\u2009+\u2009T cell cytotoxic function through the\n                    <jats:italic>SPP1\u2011CD44<\/jats:italic>\n                    signaling axis, as demonstrated by in\n                    <jats:italic>vitro<\/jats:italic>\n                    co\u2011culture assays, a large\u2011scale tissue microarray, and multiple syngeneic mouse models. Spatially, they are scattered throughout the tumour and form dense barriers that sequester CD8\u2009+\u2009T cells and drive their exhaustion. Strikingly, this spatial configuration inversely correlates with cytotoxic activity and adaptive immune signatures and thereby reinforces a local immunosuppressive niche that sustains chemoresistance. These data provide the missing link: effective chemotherapy requires an immune\u2011active hepatic microenvironment, and\n                    <jats:italic>SPP1<\/jats:italic>\n                    \u2009+\u2009macrophage infiltration actively disrupts this state, which in turn promotes clinical resistance. In a preclinical CRLM model, SPP1 blockade synergised with anti\u2011PD\u20111, inducing significant tumour regression and restoring T\u2011cell function. Collectively, our findings position\n                    <jats:italic>SPP1<\/jats:italic>\n                    \u2009+\u2009macrophages as central drivers of NAC resistance in CRLM and highlight the spatial immune barrier they create as a promising therapeutic target for overcoming chemoresistance and improving immunotherapy responses.\n                  <\/jats:p>","DOI":"10.1186\/s43556-026-00581-7","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T02:23:27Z","timestamp":1791167007000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Characterization of SPP1\u2009+\u2009macrophages and their correlation with resistance to neoadjuvant chemotherapy in colorectal cancer liver metastasis"],"prefix":"10.1186","volume":"7","author":[{"given":"Jingzhi","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijie","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xigan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linjie","family":"Ruan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyao","family":"Quan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5849-2368","authenticated-orcid":false,"given":"Shichong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"issue":"1","key":"581_CR1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3322\/caac.21820","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel RL, Giaquinto AN, Jemal A. 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All protocols for animal use and euthanasia were reviewed and approved by the Department of Laboratory Animal Science, Fudan University Animal Care and Ethics Committee (202307010S).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"194"}}