Therapeutic reprogramming of tumour-associated macrophages in pancreatic cancer using a cytotoxic CCR2-targeted nanotheranostic.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits a profoundly immunosuppressive tumour microenvironment (TME) dominated by inflammatory monocytes (IMs) and tumour-associated macrophages (TAMs), which restrict adaptive immunity and drive resistance to immune checkpoint blockade (ICB). Recruitment of CCR2⁺ 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. METHODS: 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. RESULTS: C-E-G exhibited robust tumour accumulation and selectively eliminated CCR2⁺ TAMs without systemic myelotoxicity, while durably reprogramming residual macrophages. Mechanistically, C-E-G induced the emergence of an immunostimulatory CCRL2⁺ TAM subset through true macrophage repolarization rather than monocyte replacement. CCRL2⁺ TAMs accumulated intratumoural chemerin, upregulated antigen-presentation and co-stimulatory programs, and were essential for CD8⁺ 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. CONCLUSIONS: CCR2-targeted cytotoxic nanotherapy eliminates immunosuppressive CCR2 + TAMs, reprograms the macrophage landscape including CCRL2⁺ TAMs, and unlocks durable anti-tumour immunity in PDAC, supporting translational development of this strategy.