{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:57:51Z","timestamp":1792789071761,"version":"4.5.0"},"reference-count":114,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T00:00:00Z","timestamp":1599004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SFB","award":["1066"],"award-info":[{"award-number":["1066"]}]},{"name":"Collaborative Research Center (CRC)","award":["1292 (project B8)"],"award-info":[{"award-number":["1292 (project B8)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cathepsin S (CatS) is a secreted cysteine protease that cleaves certain extracellular matrix proteins, regulates antigen presentation in antigen-presenting cells (APC), and promotes M2-type macrophage and dendritic cell polarization. CatS is overexpressed in many solid cancers, and overall, it appears to promote an immune-suppressive and tumor-promoting microenvironment. While most data suggest that CatS inhibition or knockdown promotes anti-cancer immunity, cell-specific inhibition, especially in myeloid cells, appears to be important for therapeutic efficacy. This makes the design of CatS selective inhibitors and their targeting to tumor-associated M2-type macrophages (TAM) and DC an attractive therapeutic strategy compared to the use of non-selective immunosuppressive compounds or untargeted approaches. The selective inhibition of CatS can be achieved through optimized small molecule inhibitors that show good pharmacokinetic profiles and are orally bioavailable. The targeting of these inhibitors to TAM is now more feasible using nanocarriers that are functionalized for a directed delivery. This review discusses the role of CatS in the immunological tumor microenvironment and upcoming possibilities for a nanocarrier-mediated delivery of potent and selective CatS inhibitors to TAM and related APC to promote anti-tumor immunity.<\/jats:p>","DOI":"10.3390\/cells9092021","type":"journal-article","created":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T09:29:28Z","timestamp":1599038968000},"page":"2021","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Novel Opportunities for Cathepsin S Inhibitors in Cancer Immunotherapy by Nanocarrier-Mediated Delivery"],"prefix":"10.3390","volume":"9","author":[{"given":"Natalie","family":"Fuchs","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University of Mainz, Staudingerweg 5, D, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3601-9523","authenticated-orcid":false,"given":"Mergim","family":"Meta","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University of Mainz, Staudingerweg 5, D, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Detlef","family":"Schuppan","sequence":"additional","affiliation":[{"name":"Institute of Translational Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 63, 55131 Mainz, Germany"},{"name":"Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lutz","family":"Nuhn","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Polymer Research Ackermannweg 10, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Schirmeister","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University of Mainz, Staudingerweg 5, D, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.celrep.2020.107522","article-title":"Cathepsin S Alterations Induce a Tumor-Promoting Immune Microenvironment in Follicular Lymphoma","volume":"31","author":"Bararia","year":"2020","journal-title":"Cell Rep."},{"key":"ref_2","first-page":"99","article-title":"Cathepsin S as a target in gastric cancer (Review)","volume":"12","author":"Mattos","year":"2019","journal-title":"Mol. 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