Abstract A048: Targeting M2 macrophage polarization: The anti-tumor effects of IL-4/IL-13 blocking peptide (KROS-401) and iron oxide nanoparticles

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor, with a five-year survival rate of only 5-7%. Current therapies include surgery, chemotherapy, and radiation, but there is an urgent need for alternative strategies to reduce the side effects of these treatments. The paradigm of cancer treatment is shifting toward immunotherapy, which offers tumor target specificity through mechanisms that target specific antigen and receptors. Macrophages play a major role in innate immune system, primarily through phagocytosis and the destruction of harmful organisms. In cancer, they comprise the highest cell concentration among immune cells in the tumor microenvironment (TME). However, most of these macrophages possess pro-tumoral and immunosuppressive (M2-like) phenotype which promotes angiogenesis, tumor invasion and aid in metastasis. Tumor associated macrophages (TAMs) represent the predominant infiltrating immune cell population in gliomas, accounting for 30–50% of the total tumor cell population, and are associated with poor prognosis and higher tumor grades. M1-like TAMs produce proinflammatory cytokines that inhibit tumor progression whereas M2-like TAMs contribute to an immunosuppressive microenvironment, facilitating tumor growth. Hence, inhibition of M2 polarization could be a promising strategy to create a proinflammatory state (M1). We developed a peptide inhibitor, KROS-401, targeting the shared IL-4Ra subunit of the IL-4 and IL-13 receptor complex, aiming to inhibit macrophage polarization to the M2 phenotype and reprogram the immunosuppressive TME. Initially, we derived and differentiated macrophages from human peripheral blood mononuclear cell (PBMC) and characterized for M2 surface markers. These differentiated macrophages demonstrated excellent phagocytotic activity using red zymosan. Subsequently we assessed the effect of KROS-401 on M2 macrophage polarization. Our preliminary results showed decrease in the M2 macrophage population in a dose-dependent manner in the presence of IL-4 and IL-13. Furthermore, our in vivo studies indicated that KROS-401 had an anti-tumor effect in glioma bearing mice, with treated mice showed significantly extended overall survival compared to control group. It is reported that iron oxide nanoparticles can skew macrophages towards the M1 phenotype but no studies have explored their potential for reprogramming macrophages in glioblastoma treatment. To enhance the efficacy of KROS-401 and further reprogram the macrophage/microglia population, we developed an iron oxide nanoparticle conjugated to KROS-401. Preliminary in vitro and in vivo studies shows that the iron oxide nanoparticle conjugated to KROS-401 is safe and may effectively reprogram macrophages to inhibit tumor growth. Citation Format: Dnyaneshwar Kalyane, John Yu, Tesfahun Admasu, Michelot Michel, Hongqiang Wang, Ramachandran Murali. Targeting M2 macrophage polarization: The anti-tumor effects of IL-4/IL-13 blocking peptide (KROS-401) and iron oxide nanoparticles [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A048.