{
  "abstract": "Background The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is heavily infiltrated by inflammatory monocytes (IMs) and tumor-associated macrophages (TAMs), which suppress adaptive immunity and limit the efficacy of immune checkpoint blockade (ICB). A well-characterized mechanism involves PDAC cell-derived C-C motif chemokine ligand 2 (CCL2), which recruits C-C chemokine receptor type 2 (CCR2)-expressing IMs from the bone marrow into the TME, where they subsequently differentiate into TAMs. However, clinical trials combining small-molecule CCR2 inhibitors and ICB have struggled to achieve clinically meaningful efficacies, despite reducing intratumoral TAMs.Methods To address this translational gap, we engineered a novel nanotheranostic, in which a CCR2-binding peptide (ECL1i) and gemcitabine (GEM) are both conjugated to a copper nanocluster (CuNCs-ECL1i-GEM, or C-E-G). Radiolabelling C-E-G with 64Cu was performed to track biodistribution and tumor targeting. Efficacy studies were conducted across multiple mouse models, including the highly desmoplastic autochthonous p48-Cre;Trp53^flox/flox^ LSL-Kras^G12D^ (KPPC) mice.Results Radiolabeled C-E-G demonstrated efficient tumor accumulation in all tested mouse models. C-E-G not only significantly reduced intratumoral TAMs but also reprogrammed the remaining population into C-C motif chemokine receptor-like 2 (CCRL2)-expressing subsets. These CCRL2+ TAMs were found to bind and accumulate intratumoral chemerin, a chemoattractant for CD8+ T cells. This population was critical for recruiting and activating intratumoral CD8+ T cells. Consequently, combining C-E-G with ICB induced sustained regression of PDAC xenografts and significantly extended survival in KPPC mice.Conclusions We have developed a CCR2-targeted nanotheranostic (C-E-G) with strong preclinical efficacy. The ability of C-E-G to deplete and reprogram TAMs while enhancing CD8+ T cell recruitment and activation supports its potential as a novel immunotherapeutic strategy. These findings justify further clinical investigation in patients with PDAC.",
  "authors": [
    {
      "affiliations": [
        "Washington University School of Medicine, St Louis, MO, USA"
      ],
      "name": "Vikas Kumar Somani"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, St Louis, MO, USA"
      ],
      "name": "Xiaohui Zhang"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, St Louis, MO, USA"
      ],
      "name": "Hung-Po Chen"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, St Louis, MO, USA"
      ],
      "name": "Ashnafi Bulle"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, St Louis, MO, USA"
      ],
      "name": "Liang-I Kang"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, St Louis, MO, USA"
      ],
      "name": "David DeNardo"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, St Louis, MO, USA"
      ],
      "name": "Liu Yongjian"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, St Louis, MO, USA"
      ],
      "name": "Kian-Huat Lim"
    }
  ],
  "title": "1026 Therapeutic reprogramming of tumor-associated macrophages in pancreatic cancer using a cytotoxic CCR2-targeted nanotheranostic",
  "uid": "3798777a-84f8-50b3-88f3-279361cf6e58"
}