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Increasing evidence suggests that metastatic dissemination and resistance to treatment are sustained by systemic immune dysfunction and vascular remodeling. Yet, the underpinning mechanisms remain incompletely understood. Therefore, we applied a multilayered liquid biopsy strategy to characterize the systemic immunovascular landscape of mBC and identify clinically actionable circulating biomarkers of disease progression and risk stratification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this prospective study, peripheral blood samples were collected from 60 patients at diagnosis of stage IV mBC before treatment initiation. Circulating tumor cells (CTCs) were enumerated with the CellSearch\n                      <jats:sup>\u00ae<\/jats:sup>\n                      system. Immune profiling was performed by flow cytometry, and plasma proteomic analysis using the Olink\n                      <jats:sup>\u00ae<\/jats:sup>\n                      96 Immuno-Oncology panel. Progression-free survival (PFS) was analyzed using Kaplan\u2013Meier and Cox proportional hazards models, including multivariate analysis to identify independent prognostic factors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Tumors were mainly HR\u207a\/HER2\u207b (83.3%), and the median follow-up and progression-free survival (PFS) were 31.5 months and 19.9 months, respectively. CTCs were detected in 58.3% of patients (range: 1\u2013962 CTCs\/7.5 mL blood). Comprehensive immune profiling revealed that total leukocytes and CD3\u207a T cells were strongly reduced and regulatory T cells (Tregs; CD4\u207aCD25\n                      <jats:sup>high<\/jats:sup>\n                      CD127\n                      <jats:sup>low\/\u2013<\/jats:sup>\n                      ), which expressed various inhibitory receptors (PD-1, CTLA-4, TIGIT, LAG-3), were increased in patient\u2019s vs. age-matched healthy donors. The co-expression of PD-1, CTLA-4, LAG-3 and TIGIT in effector T cells (CD4\u207a, CD8\u207a) indicated exhaustion. Circulating monocytes\/macrophages exhibited a shift toward the immunosuppressive CD163\u207aCD206\u207a phenotype. Plasma proteomic profiling identified an inflammatory and angiogenic signature (elevated IL-6, IL-8, HGF, ANGPT2, NOS3, CSF1 and galectin-9, and reduced FASLG and TWEAK expression). Notably, Treg proportion and IL-8, HGF, galectin-9 and TNFRSF12A levels were higher in CTC-positive than CTC-negative patients. Liver metastases, triple-negative receptor status, and high CTC count predicted shorter PFS. Multivariate Cox analysis identified IL-8 (HR\u2009=\u20091.49,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.004) and NOS3 (HR\u2009=\u20094.72,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.003) as independent PFS predictors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This integrated cellular and proteomic liquid biopsy approach showed that mBC is a systemic immunovascular disease characterized by T-cell exhaustion, Treg expansion, TIGIT-mediated cytotoxic restraint, monocyte polarization, pro-angiogenic cytokine milieu and CTC-mediated immune escape. Circulating IL-8 and NOS3 may represent blood-based prognostic biomarkers and therapeutic targets in mBC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>NCT04025541 registered on July 19, 2019.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03709-3","type":"journal-article","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T04:15:58Z","timestamp":1776485758000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Liquid biopsy reveals the immune status and protein profiles linked to CTC burden and clinical outcomes in metastatic breast cancer"],"prefix":"10.1186","volume":"45","author":[{"given":"Keerthi","family":"Kurma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Bardol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Mollevi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Eslami-S","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Garima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Alexandre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang\u00e9lique","family":"Bobrie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Lossaint","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blandine","family":"Massemin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"D\u2019Hondt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9verine","family":"Guiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Cayrefourcq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Jacot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Alix-Panabi\u00e8res","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,18]]},"reference":[{"issue":"6024","key":"3709_CR1","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.1126\/science.1203543","volume":"331","author":"CL Chaffer","year":"2011","unstructured":"Chaffer CL, Weinberg RA. 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Cancer Discov. 2021;11(4):838\u201357.","journal-title":"Cancer Discov"}],"container-title":["Journal of Experimental &amp; Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13046-026-03709-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-026-03709-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-026-03709-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T22:20:03Z","timestamp":1781648403000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13046-026-03709-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,18]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3709"],"URL":"https:\/\/doi.org\/10.1186\/s13046-026-03709-3","relation":{},"ISSN":["1756-9966"],"issn-type":[{"value":"1756-9966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,18]]},"assertion":[{"value":"6 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All patients provided their written informed consent and were prospectively included in the ethics committee-approved (CPP Ouest 4) ALCINA 2 study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Catherine Alix\u2010Panabi\u00e8res is one of the patent holders (US Patent Number 16,093,934) for detecting and\/or characterizing circulating tumor cells. She received an honorarium from Menarini\u00a9. William Jacot is on the Astra Zeneca, Eisai, BMS, Lilly France, Daiichi Sankyo, MSD, Novartis, Pfizer, Roche, and Seagen advisory boards and received honoraria or payment from Astra Zeneca, Eisai, BMS, Lilly France, Daiichi Sankyo, MSD, Novartis, Pfizer, Roche and Seagen. William Jacot also received meeting travel support from Astra Zeneca, Novartis, Chugai Pharma, Pfizer, Eisai, Pierre Fabre, Glaxo SmithKline, Roche, Lilly France, Sanofi, and Aventis. The remaining authors declare no conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"111"}}