{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:13:29Z","timestamp":1785420809948,"version":"3.56.0"},"reference-count":34,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS","award":["JP24K11929"],"award-info":[{"award-number":["JP24K11929"]}]},{"name":"JSPS","award":["JP24K02519"],"award-info":[{"award-number":["JP24K02519"]}]},{"name":"JSPS","award":["JP23K19635"],"award-info":[{"award-number":["JP23K19635"]}]},{"name":"JSPS","award":["JP25K23990"],"award-info":[{"award-number":["JP25K23990"]}]},{"award":["JP24K11929"],"award-info":[{"award-number":["JP24K11929"]}],"id":[{"id":"https:\/\/ror.org\/02m7axw05","id-type":"ROR","asserted-by":"publisher"}]},{"award":["JP24K02519"],"award-info":[{"award-number":["JP24K02519"]}],"id":[{"id":"https:\/\/ror.org\/02m7axw05","id-type":"ROR","asserted-by":"publisher"}]},{"award":["JP23K19635"],"award-info":[{"award-number":["JP23K19635"]}],"id":[{"id":"https:\/\/ror.org\/02m7axw05","id-type":"ROR","asserted-by":"publisher"}]},{"award":["JP25K23990"],"award-info":[{"award-number":["JP25K23990"]}],"id":[{"id":"https:\/\/ror.org\/02m7axw05","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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-na\u00efve 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\u2013qPCR). 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-na\u00efve 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.<\/jats:p>","DOI":"10.3390\/cancers18101635","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T11:53:10Z","timestamp":1779191590000},"page":"1635","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Paquinimod Targeting of the S100A8\/A9 Axis Suppresses Liver Metastasis in Aged Mice"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4006-8267","authenticated-orcid":false,"given":"Takao","family":"Tsuneki","sequence":"first","affiliation":[{"name":"Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa 359-8513, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4208-7138","authenticated-orcid":false,"given":"Kimihiro","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan"},{"name":"Department of Biophysics, Graduate School of Health Sciences, Kobe University, Kobe 654-0142, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Ando","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Shirakami","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Ito","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukari","family":"Adachi","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Kagiyama","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Tachibana","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Imai","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0541-4942","authenticated-orcid":false,"given":"Sachiko","family":"Inubushi","sequence":"additional","affiliation":[{"name":"Division of Breast Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8981-5817","authenticated-orcid":false,"given":"Kazuki","family":"Kanayama","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Graduate School of Health Sciences, Kobe University, Kobe 654-0142, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3022-8466","authenticated-orcid":false,"given":"Yu-Ichiro","family":"Koma","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Graduate School of Health Sciences, Kobe University, Kobe 654-0142, Hyogo, 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9154-4972","authenticated-orcid":false,"given":"Naoki","family":"Urakawa","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4337-5529","authenticated-orcid":false,"given":"Hironobu","family":"Goto","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe 650-0017, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1545-0509","authenticated-orcid":false,"given":"Hiroshi","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Division of Gastrointestinal Surgery, Department of Surgery, 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s12943-024-02020-z","article-title":"Aging and Cancer","volume":"23","author":"Kroemer","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4293","DOI":"10.1200\/JCO.23.00933","article-title":"Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy: ASCO Guideline Update","volume":"41","author":"Dale","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1007\/s00384-018-3163-y","article-title":"Frailty in Surgical Patients","volume":"33","author":"Richards","year":"2018","journal-title":"Int. J. Color. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.tipsro.2020.09.001","article-title":"Personalised Treatment for Older Adults with Cancer: The Role of Frailty Assessment","volume":"16","author":"Leech","year":"2020","journal-title":"Tech. Innov. Patient Support Radiat. 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