Abstract 5220: Regulating tumor-associated macrophage polarization via inhibition of hedgehog signaling for treating colorectal cancer liver metastasis

Abstract Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related mortality worldwide. The liver is the most frequent site of metastasis in patients with CRC. Approximately 15-25% of patients with CRC have synchronous liver metastasis (LM). Despite the development of surgical techniques and targeted therapy, the prognosis of colorectal cancer liver metastasis (CRLM) remains poor. The tumor microenvironment (TME) is composed of cancerous and non-cancerous cells, including fibroblasts, endothelial cells and immune cells, as well as non-cellular components. As a major component of immune cells in the TME, tumor-associated-macrophages (TAMs) account for up to 50% of cells in the tumor mass and are generally relevant to worse prognosis in cancer patients. TAMs are an important component of the immunosuppressive TME, but the precise mechanisms of the interactions between TAMs and tumor cells are still not completely understood. The hedgehog (Hh) signaling pathway is aberrantly activated in multiple types of human cancer. Hh signaling pathway plays an important role in tumorigenesis, including promoting tumor invasion, metastasis, and multi-drug resistance. However, it remains to be elucidated how Hh ligands ac on stromal cells within the TME to promote tumor growth and what cell types are involved in this process. In this study, we established an irinotecan-resistant colorectal cancer cell lines to represent liver metastatic colorectal cancer. We then found that irinotecan-resistant colorectal cancer cells significantly increased SHH secretion using quantitative reverse transcription PCR (qRT-PCR) and an ELISA assay. Subsequently, we used a THP-1 and bone marrow-derived monocytes (BMDMs) to determine whether Hh signaling and metastatic colorectal cancer cells affect the polarization and activity of macrophages. We found that tumor cells-derived SHH induced M2 polarization of TAMs under tumor cells-derived conditioned medium and co-culture systems using Western blot and Flow cytometry analysis. Moreover, phagocytosis ability of macrophages was decreased with irinotecan-resistant colorectal cancer cells compared with irinotecan-parent colorectal cancer cells under co-culture systems. To further investigate whether inhibition of Hh signaling affects macrophage polarization, we treated with Vismodegib, a Hh signaling inhibitor. M2 macrophage polarization increased by SHH was reduced by Hh signaling inhibitor treatment. Furthermore, TISIDB revealed that SHH was strongly negatively correlated with macrophage abundance and CD80, CD86 in COAD patients In conclusion, our study identified a novel mechanism for macrophage polarization through Shh signaling pathway and provided insights into developing macrophage-targeted therapeutic strategies for CRLM patients. Citation Format: Bu Gyeom Kim, Bo Ram Kim, Dae Yeong Kim, Hyemi Yun, Okhyeon Kim, Yoon Namgung, Jun Woo Bong, Sanghee Kang, Sun Il Lee, Sang Cheul Oh. Regulating tumor-associated macrophage polarization via inhibition of hedgehog signaling for treating colorectal cancer liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5220.