Mitochondrial Enzyme A Promotes Macrophage-Dependent Antitumor Responses in Colorectal Cancer

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, with the immunosuppressive tumor microenvironment (TME) posing a major barrier to effective therapy. Previous studies have shown that the mitochondrial enzyme A promotes CRC progression and may represent a potential therapeutic target. However, enzyme A is also highly expressed in M1 macrophages, where it drives inflammatory gene expression, underscoring the need to clarify its role specifically within tumor-associated macrophages (TAMs). Our findings demonstrate that mice with a global deletion of enzyme A develop significantly larger tumors compared to littermate controls. Similarly, LysMcre mediated macrophage-specific knockout mice displayed a marked increase in tumor burden. Moreover, adoptive transfer of bone marrow-derived macrophages (BMDMs) suppressed tumor growth and prolonged survival, whereas enzyme A-deficient BMDMs failed to exert these antitumor effects. These results indicate that macrophage-intrinsic enzyme A is essential for effective antitumor immunity. Mechanistically, enzyme A deficiency in macrophages resulted in reduced frequencies and total numbers of IFN-γ+, TNF-α+, and granzyme B+ tumor-infiltrating NK cells, indicating impaired NK-cell activation and cytotoxic function. Further analysis revealed that enzyme A regulates the expression of key macrophage-derived cytokines and chemokines, including Ccl2, Cxcl9/10, and Il12, that are critical for NK-cell recruitment and functional activation. Citation Format: Lin Chung, Shi-Chuen Miaw, . Mitochondrial enzyme A promotes macrophage-dependent antitumor responses in colorectal cancer [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 1593.