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Recruitment of CCR2\u207a IMs by tumour-derived CCL2 is a central mechanism underlying TAM accumulation. Conventional gemcitabine (GEM) and small-molecule CCR2 inhibitors provide limited benefit due to poor intratumoural delivery, transient target engagement, and compensatory myeloid recruitment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We engineered a CCR2-targeted nanotheranostic by conjugating a CCR2-binding peptide (ECL1i) and GEM onto ultrasmall copper nanoclusters (CuNCs-ECL1i-GEM; C-E-G). Therapeutic efficacy and immune remodelling were evaluated using orthotopic subcutaneous and the autochthonous PDAC mouse models model, using scRNAseq, flow cytometry, multiplex immunohistochemistry, and in vitro functional assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>C-E-G exhibited robust tumour accumulation and selectively eliminated CCR2\u207a TAMs without systemic myelotoxicity, while durably reprogramming residual macrophages. Mechanistically, C-E-G induced the emergence of an immunostimulatory CCRL2\u207a TAM subset through true macrophage repolarization rather than monocyte replacement. CCRL2\u207a TAMs accumulated intratumoural chemerin, upregulated antigen-presentation and co-stimulatory programs, and were essential for CD8\u207a T-cell recruitment and activation. Genetic and orthotopic studies confirmed their CCR2-independent origin and requirement for tumour control. C-E-G remodelled the TME toward a lymphocyte-permissive inflammatory state and synergized with ICB to induce complete tumour regression and prolong survival in KPPC mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CCR2-targeted cytotoxic nanotherapy eliminates immunosuppressive CCR2\u2009+\u2009TAMs, reprograms the macrophage landscape including CCRL2\u207a TAMs, and unlocks durable anti-tumour immunity in PDAC, supporting translational development of this strategy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12943-026-02597-7","type":"journal-article","created":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T13:34:52Z","timestamp":1770471292000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Therapeutic reprogramming of tumour-associated macrophages in pancreatic cancer using a cytotoxic CCR2-targeted nanotheranostic"],"prefix":"10.1186","volume":"25","author":[{"given":"Vikas Kumar","family":"Somani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy Hung-Po","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashenafi","family":"Bulle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sapana","family":"Bansod","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Geng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang-I","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyu Seong","family":"Heo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Luehmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuena","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad A.","family":"Saeed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kory J.","family":"Lavine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"DeNardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell K.","family":"Pachynski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kian-Huat","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,7]]},"reference":[{"key":"2597_CR1","doi-asserted-by":"crossref","unstructured":"Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, et al. 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Consent to participate is not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"65"}}