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However, mononuclear phagocyte system\u2010mediated clearance of liposome encapsulated Re188 (Lipo\u2010Re188) limits its tumor delivery. This study aimed to enhance the therapeutic effect of Lipo\u2010Re188 against lung metastases through macrophage depletion and immune checkpoint blockade. A lung metastatic colon cancer model was established via intravenous injection of CT26\u2010luciferase cells and then treated with Lipo\u2010Re188 (11.1\u2009MBq, 30% of MTD), liposomal clodronate (Lipo\u2010clod) for macrophage depletion, and\/or anti\u2010PD\u2010L1 antibody. Tumor progression was monitored by bioluminescence imaging, and radionuclide biodistribution was assessed at 1, 24, and 48\u2009h post\u2010injection. Flow cytometry was used to assess immune cell populations in the spleen and tumor microenvironment (TME). Cytokine levels were measured using a bead\u2010based multiplex assay and analyzed by flow cytometry. Macrophage depletion significantly enhanced tumor accumulation of Lipo\u2010Re188 while reducing hepatic uptake and prolonging survival. The combination of Lipo\u2010clod and Lipo\u2010Re188 promoted B cells, restored functional T cells, and suppressed MDSC in both spleen and TME. Notably, IL\u20101\u03b1 and GM\u2010CSF levels were significantly elevated in the combination group. Triple therapy with Lipo\u2010clod, Lipo\u2010Re188, and anti\u2010PD\u2010L1 provided the greatest survival benefit, highest intratumoral B cell accumulation, and lowest interstitial macrophage levels, with no significant biological toxicity. Our study reveals that triple therapy overcomes immunosuppressive feedback and promotes a tumor\u2010suppressive microenvironment. These findings support a rational combination strategy integrating radiopharmaceutical therapy with immune modulation for metastatic cancer treatment.<\/jats:p>","DOI":"10.1111\/cas.70206","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T09:31:19Z","timestamp":1758533479000},"page":"3442-3458","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Liposomal\n                    <scp>\n                      <sup>188<\/sup>\n                      Rhenium\n                    <\/scp>\n                    Plus Macrophage Depletion Enhances Anti\u2010\n                    <scp>PD<\/scp>\n                    \u2010\n                    <scp>L1<\/scp>\n                    Efficacy and B Cell Infiltration Against Lung Metastatic Cancer"],"prefix":"10.1111","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1015-6503","authenticated-orcid":false,"given":"Shin\u2010Yi","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Biomedical Imaging and Radiological Science China Medical University  Taichung Taiwan"},{"name":"Graduate Institute of Biomedical Sciences China Medical University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang\u2010Ting","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Health Technology and Informatics The Hong Kong Polytechnic University  Kowloon Hong Kong"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chih\u2010Hsien","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Isotope Application Research National Atomic Research Institute  Taoyuan 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