Abstract
BACKGROUND: Colorectal cancer liver metastasis (CRLM) remains a major challenge in oncology, with the tumor microenvironment playing a crucial role in disease progression. This study investigates the function of the Tripartite Motif Containing 26 (TRIM26) in the CRLM microenvironment, focusing on its regulation of tumor-associated macrophage (TAM) polarization and its implications for metastatic growth. METHODS: Using established mouse CRLM models, we characterized TAM phenotypes using flow cytometry and immunohistochemistry. In vitro co-culture experiments evaluated the effects of Trim26-deficient bone marrow-derived macrophages (BMDMs) on tumor cell behavior. Western blotting and luciferase reporter assays were employed to elucidate the underlying molecular mechanisms. RESULTS: Trim26 knockout mice exhibited significantly reduced liver metastasis and an increased proportion of M1-like TAMs. Trim26-deficient BMDMs suppressed tumor cell migration and proliferation. TRIM26 modulates macrophage polarization by inhibiting the NF-κB signaling pathway. Specifically, TRIM26 interacts with TRAF2 through its PRY domain and inhibits the K63-linked ubiquitination of TRAF2, thereby attenuating NF-κB pathway activation. Furthermore, clinical CRLM samples revealed a negative correlation between TRIM26 expression and M1-like TAM infiltration. CONCLUSION: We identified TRIM26 as a potential therapeutic target for CRLM, providing novel insights into tumor-stromal microenvironment interactions and offering new strategies to improve patient outcomes.