Paquinimod Targeting of the S100A8/A9 Axis Suppresses Liver Metastasis in Aged Mice

Background: Aging profoundly alters host immunity, yet how age-associated immune changes in the liver influence the growth of metastatic tumors remains incompletely understood. Liver metastasis is a major cause of cancer-related mortality, particularly in elderly patients, for whom aggressive treatments are often not feasible. This study aimed to clarify how aging reshapes the hepatic immune microenvironment and to identify age-associated host factors that influence liver metastasis growth. Methods: Tumor-naïve and tumor-bearing young and aged mice were analyzed using a syngeneic MC38 liver metastasis model. Immune cell composition in the liver was assessed by flow cytometry, and gene expression was evaluated by quantitative reverse transcription PCR (RT-qPCR). Public transcriptomic datasets were screened to identify age-associated inflammatory factors. The functional relevance of the S100A8/A9 axis was examined using the small-molecule inhibitor paquinimod. Results: Aging was associated with a distinct baseline immune cell composition in the liver. During liver metastasis, overall growth was comparable between young and aged mice; however, metastatic lesions in aged hosts showed increased expression of multiple inflammation-related genes and prominent accumulation of Ly6G⁺ cells. In silico screening identified S100a9 as one of the most highly upregulated inflammation-related genes in aged livers, which was confirmed in both tumor-naïve and metastatic liver tissues. Pharmacological modulation of the S100A8/A9 axis with paquinimod significantly reduced liver metastasis growth in aged, but not young, mice, and was accompanied by a shift in immune cell composition, including an increased representation of CD8⁺ T cells. Conclusions: These findings indicate that aging is associated with a distinct hepatic immune context that shapes the inflammatory and cellular composition of the tumor microenvironment during liver metastasis. S100A9 emerges as a key age-associated, host-derived factor that is functionally relevant to the growth of liver metastases in aged hosts, supporting the S100A8/A9 axis as a context-specific therapeutic target.