Abstract 6607: HDAC6 inhibition modulates macrophage function in the post-radiation therapy tumor microenvironment.

Abstract Historically, radiation therapy (RT) is the mainstay of cancer therapy, with more than half of the cancer patients receiving RT during the course of their treatment. Besides killing cancer cells by DNA damage, RT also induces immunogenic tumor cell death and reshapes the local antitumor immune response. Often, tumor-associated macrophages (TAMs) play a key role in regulating the innate antitumor immune response within the tumor microenvironment (TME). Post-RT, due to their phenotypic plasticity, TAMs often shift between a pro-inflammatory M1-like phenotype and immunosuppressive tumor-promoting M2-like state. Furthermore, these M2-polarized TAMs recruit circulating monocytes and tissue-resident macrophages into the tumor. This results in negating the therapeutic benefit of RT by promoting tumor growth and metastasis. Therefore, strategies to reprogram TAMs are critical to the success of RT. Our lab has reported that targeting Histone Deacetylase 6 (HDAC6) with isoform-specific inhibitors in macrophages can suppress the M2-like phenotype within the TME. We explored one of several molecular mechanisms underlying the interplay among tumor cells, macrophages, and tumor-infiltrating immune cells.First, we demonstrated that M2-like macrophages migrate toward irradiated tumor cells at a significantly higher rate than M1-like macrophages, a migration that was suppressed by the HDAC6 inhibitor SP-2-225. To unravel the factors involved in the macrophage migration, we analyzed a panel of 38 cytokines and chemokines from the co-culture assay. The data revealed that macrophages irradiated with a single dose of 6Gy significantly increased the expression of CCL5 chemokine. Also, co-culture with irradiated macrophages promoted the proliferation of 4T1 breast cancer tumor cells. In addition, qPCR and flow cytometry analyses showed that SP-2-225 suppressed the expression of CCL5 receptor, CCR5, on macrophages, providing a potential mechanism for the reduced migration. Furthermore, the in vivo combination of SP-2-225 and 6Gy of RT on the syngeneic murine 4T1 triple-negative breast cancer model demonstrated that mice receiving the combination therapy exhibited improved tumor control and delayed post-RT relapse. Overall, these findings suggest that targeting the CCL5-CCR5 axis with an HDAC6 inhibitor in TAMs post-irradiation may enhance the therapeutic efficacy of radiation therapy. Citation Format: Xintang Li, Satish K. Noonepalle, Sonia Sebaoui, Manasa Suresh, Marie Durr, Bryan Weselman, Vidhi Sharma, Danae K. Boikos, Zazing Mawi, Gabriella Rigoli, Armijo Marisol. E, Scott Grindrod, Anatoly Dritschilo, Alejandro Villagra. HDAC6 inhibition modulates macrophage function in the post-radiation therapy tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6607.