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

  • Cancers (Basel). 2026 May 19;18(10):1635. doi: 10.3390/cancers18101635.
Takao Tsuneki  1 ,  Masafumi Saito  2 ,  Kimihiro Yamashita  1  3 ,  Masayuki Ando  1 ,  Keisuke Yasuda  1 ,  Naoto Shirakami  1 ,  Ryota Ito  1 ,  Yukari Adachi  1 ,  Hiroki Kagiyama  1 ,  Takaaki Tachibana  1 ,  Masaki Imai  1 ,  Sachiko Inubushi  4 ,  Kazuki Kanayama  3 ,  Yu-Ichiro Koma  3 ,  Mitsugu Fujita  1  5 ,  Joerg-Matthias Pollok  6 ,  Yutaka Sugita  1 ,  Taro Ikeda  1 ,  Yasufumi Koterazawa  1 ,  Tomoaki Aoki  1 ,  Hitoshi Harada  1 ,  Yasunori Otowa  1 ,  Naoki Urakawa  1 ,  Hironobu Goto  1 ,  Hiroshi Hasegawa  1 ,  Shingo Kanaji  1 ,  Takeru Matsuda  1 ,  Yoshihiro Kakeji  1
Affiliations
  • 1. Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan.
  • 2. Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa 359-8513, Saitama, Japan.
  • 3. Department of Biophysics, Graduate School of Health Sciences, Kobe University, Kobe 654-0142, Hyogo, Japan.
  • 4. Division of Breast Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan.
  • 5. Center for Medical Education and Clinical Training, Faculty of Medicine, Kindai University, Higashiosaka 577-8502, Osaka, Japan.
  • 6. Division of Surgery and Interventional Science, Faculty of Medical Sciences, University College London, London NW3 2QG, UK.
PMID: 42192994 DOI: 10.3390/cancers18101635
Abstract

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.

Keywords
CD8+ T cells; S100A8/A9 axis; aging; hepatic immune microenvironment; liver metastasis; myeloid immune cells; paquinimod.
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