Abstract A105: Therapeutic Reprogramming Of Tumor-Associated Macrophages In Pancreatic Cancer Using A Cytotoxic CCR2-Targeted Nanotheranostic

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. An approach to address this translational gap is by developing a more efficacious therapeutic that can eliminate, rather than transiently suppress, CCR2+ TAMs. To this end, 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 demonstrated efficient tumor accumulation across multiple mouse models, including the highly desmoplastic autochthonous p48-Cre;Trp53 flox/flox LSL-Kras G12D (KPPC) mice. C-E-G not only significantly reduces intratumoral TAMs but also reprograms the remaining population into a C-C motif chemokine receptor-like 2 (CCRL2)-expressing subsets. These CCRL2+ TAMs bind and thus accumulate intratumoral chemerin, a known chemoattractant for CD8+ T cells, and are essential 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. In summary, we have developed a CCR2-targeted nanotheranostic with strong preclinical efficacy that supports further evaluation in clinical trials for patients with PDAC. Citation Format: Vikas K. Somani, Xiaohui Zhang, Timothy Hung-Po Chen, Ashenafi Bulle, Sapana K. Bansod, Liang-I Kang, David G. DeNardo, Yongjian Liu, Kian-Huat Lim. Therapeutic Reprogramming Of Tumor-Associated Macrophages In Pancreatic Cancer Using A Cytotoxic CCR2-Targeted Nanotheranostic [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A105.