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Through novel observational methods focused on human living and fixed tissue, we profiled the spatial and molecular features of microsatellite stable (MSS) CRLM and the surrounding liver microenvironment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>First, we re-purposed normothermic hepatic machine perfusion as a preclinical model of MSS CRLM, enabling delivery of labelled T-cells through physiological vascular routes into living, tumour-bearing human livers. Second, to dissect the liver microenvironment, we spatially map the transcriptomes of MSS CRLM and adjacent liver at single-cell resolution across ~\u20091.9\u00a0million cells, and perform multiplexed immunofluorescence applying a19-marker panel to a validation cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Whilst T-cells readily extravasated within the peri-tumoural liver, they failed to extravasate into MSS CRLM. Spatial analyses revealed a progressive shift in endothelial phenotypes across regions: from a non-inflamed state in normal liver, to a highly inflamed, peri-tumoural endothelium, and finally to an anergic, angiogenic endothelial population within CRLM characterised by reduced expression of adhesion molecules required for T-cell extravasation. CD4 T-cells that extravasate in the peri-tumoural liver are TCR-reactive yet exhausted, whereas CD4 T-cells within CRLM show stress responses, impaired cytokine gene expression and reduced TCR reactivity, residing within hypoxic niches. These divergent CD4 phenotypes are associated with distinct fibroblast-myeloid niches across peri-tumoural and tumour regions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Based on these observations, MSS CRLM impair T-cell extravasation and simultaneously drive intra-tumoural endothelial anergy, peri-tumoural T-cell exhaustion and an intra-tumoural T-cell stress response. Further mechanistic work is needed to validate these findings and guide the development of novel immunotherapeutics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12943-026-02732-4","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T08:09:05Z","timestamp":1784534945000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evidence of endothelial anergy and T-cell exclusion in microsatellite stable colorectal liver metastases revealed through human hemi-liver perfusion and spatial transcriptomics"],"prefix":"10.1186","volume":"25","author":[{"given":"Peter Kok-Ting","family":"Wan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranchu","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Areeb","family":"Mian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet","family":"Hazini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sorayya","family":"Moradi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Friesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flurin","family":"Caviezel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Hussain","family":"Abbas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brannon","family":"Nicholls","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatem","family":"Sadik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adil","family":"Lakha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keaton","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girishkumar","family":"Kumaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Bottomley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Coles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Bashford-Rogers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantin","family":"Coussios","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Len","family":"Seymour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Carlisle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerry","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Gordon-Weeks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"2732_CR1","doi-asserted-by":"publisher","first-page":"233","DOI":"10.3322\/caac.21772","volume":"73","author":"RL Siegel","year":"2023","unstructured":"Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. 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Tissues were collected under ethics numbers 22\/SC\/0429 and 21\/YH\/0206. The clinical details of patients in the CosMx and Cell DIVE datasets and those in hemi-liver perfusion experiments are shown in supplementary Tables 1\u20133 respectively.","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":"RB-R: R.J.M.B.-R. is a co-founder and consultant of Alchemab Therapeutics Ltd.CC: CCC is a co-founder, director, shareholder, and receives consultancy income from OrganOx Ltd, the company that developed and commercialized for the purposes of organ preservation prior to transplantation the normothermic liver perfusion device used in the current research.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"244"}}