Abstract 3289: Radiation supports the polarization of M1 macrophages against triple-negative breast cancer cells via the IKZF1 - CCL5 axis

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Abstract Triple-negative breast cancer (TNBC), known for its therapeutic challenges and high metastatic potential, is commonly treated with ionizing radiation (IR). In the tumor microenvironment (TME) of TNBC, macrophages occupy a place and are reprogrammed into two main types, M1 and M2, in response to different stimuli such as IR or various cytokines. However, the detailed molecular mechanism remains to be elucidated. Using our cell model, we applied IR dose-dependently (0.5/8 Gy) to observe macrophage polarization and found that high-dose IR could increase the proportion of M1 macrophages. These trends are consistent with polarization by LPS (M1) and IL-4/IL-13 (M2), respectively. By integrating transcriptomics and cytokine array profiling, we demonstrated that IKAROS family zinc finger 1 (IKZF1), a transcription factor involved in DNA repair, downregulates secretion of the downstream target, CCL5, in macrophages under high-dose IR exposure. In the collected conditioned medium, the high-dose IR group could significantly inhibit the migration and proliferation of TNBC cells. Even, recombinant CCL5 protein was recruited to modulate the TME of TNBC, and the migration ability of TNBC cells was reversed. In the direct co-culture system, phagocytic event was enhanced by high-dose IR. In conclusion, under high-dose irradiation conditions, IKZF1 is inhibited and CCL5 secretion is reduced. The TME environment is conducive to polarization of the M1 subtype and enhances its ability to phagocytose TNBC cells, thereby inhibiting TNBC progression. This finding suggests that the benefits of radiotherapy in TNBC may also be linked to a new chapter in immunotherapy. Citation Format: Kuo Han-Hsi, Yu-Chan Chang. Radiation supports the polarization of M1 macrophages against triple-negative breast cancer cells via the IKZF1 - CCL5 axis [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 3289.

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