Abstract B048: Selective targeting and killing of tumor associated macrophages with a novel nanomedicine to overcome the immunosuppressive microenvironment

Abstract Tumor associated macrophages (TAMs) within the tumor microenvironment play a significant role in promoting tumor cell proliferation by suppressing the adaptive immune response. Targeting these TAMs presents a new therapeutic strategy to inhibit tumor growth. Hydroxyl dendrimers are nanoparticles with unique physicochemical properties that allow for specific targeting to activated immune cells in regions of inflammation. We sought to utilize these properties to first assess selective targeting of TAMs in a range of tumor models, and then selectively kill TAMs using a radionuclide therapeutic in an orthotopic model. First, we investigated whether dendrimer size (Generation 4 (14 kDa; HD4) vs Generation 6 (58 kDa; HD6)) would impact uptake in the orthotopic Renca model. Cells were implanted in the right kidneys and animals received intravenous administration of fluorescently labeled HD6-Cy5 or HD4-Cy5 dendrimers, and tumors were collected 8, 24, or 48 hours after injection. To determine whether HD6-Cy5 uptake was affected by tumor size, mice were subcutaneously implanted with different tumor cells (4T1, Colon26, Pan02, or B16F10) grown to either 100 mm3 or 250 mm3, intravenously injected with HD6-Cy5, and tumors were harvested 24 hours later. Uptake was quantified using fluorometric assay. For the efficacy study, mice were implanted orthotopically with 4T1 cells in the mammary fat pad and received vehicle or a hydroxyl dendrimer radionuclide therapeutic [177Lu]Lu-Tamrada (15 MBq) on Day 0 and Day 8. A subset of animals (n = 4 per group) received HD6-Cy5 injection on Day 6. Mice were euthanized on Days 12-15, and tumors were harvested and processed for immunohistochemistry to determine D6-Cy5 tumor uptake and TAM killing. HD6 demonstrated consistently higher TAM uptake compared to HD4, and TAM uptake continued to increase over time. HD6-Cy5 uptake by TAMs was not significantly affected by tumor size in the 4T1, Colon26, and Pan02 xenograft mouse models. Less HD6-Cy5 uptake was observed in B16F10 melanoma tumors, which may suggest the presence of fewer TAMs compared to the other tumors. [177Lu]Lu-Tamrada treatment dramatically suppressed tumor growth in the 4T1 orthotopic model. Histological analyses demonstrated significant uptake of HD6-Cy5 in TAMs surrounding and infiltrating the tumors in both groups. However, the [177Lu]Lu-Tamrada group had markedly fewer total TAMs within the tumor, which correlated with significantly fewer nuclei, indicating a decrease in tumor density. In addition, there were fewer inflammatory myeloid cells (monocytic and granulocytic myeloid-derived suppressor cells) with treatment, and a greater number of cells positive for cleaved caspase-3, a marker of cell death, indicating tumor necrosis. These data further our understanding of the impact of hydroxyl dendrimer size (HD6 over HD4) on targeting TAMs and the ability to screen different tumors for uptake of HD6 in TAMs. Moreover, we demonstrate the utility of targeted TAM killing in halting tumor progression by changing the immunosuppressive microenvironment. Citation Format: S. Sakura Minami, Benson Lu, Jonathan Yoshihara, Cindy Yang, Jeffrey L. Cleland. Selective targeting and killing of tumor associated macrophages with a novel nanomedicine to overcome the immunosuppressive microenvironment [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B048.