2. Academic Validation
  3. Paquinimod Targeting of the S100A8/A9 Axis Suppresses Liver Metastasis in Aged Mice

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

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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