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Increasing evidence implicates lysosomal cathepsins as important regulators of these defining features of pancreatic tumor biology. Cathepsin-dependent proteolysis and lysosome-associated signaling pathways contribute to extracellular matrix remodeling, regulate immune cell trafficking, and influence antigen processing and presentation. Beyond their classical degradative functions, cathepsins participate in stress-adaptive cellular programs linked to autophagy, metabolic regulation, and proteostasis, supporting tumor cell survival under hypoxic, nutrient-limited, and therapy-induced stress conditions. Within the tumor microenvironment, dysregulated cathepsin activity promotes immune evasion by reshaping cytokine networks, impairing effective antigen presentation, and reinforcing physical and functional barriers to cytotoxic T-cell infiltration. Collectively, these mechanisms position the lysosome\u2013cathepsin system as a central regulator of proteolytic remodeling, immune exclusion, and adaptive therapy resistance in pancreatic cancer, highlighting its potential relevance for emerging combinatorial therapeutic strategies.<\/jats:p>","DOI":"10.3390\/biom16060824","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:08:02Z","timestamp":1780535282000},"page":"824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Lysosome\u2013Cathepsin Axis in Pancreatic Cancer: Mechanisms of Stromal Remodeling, Immune Evasion, and Therapy Resistance"],"prefix":"10.3390","volume":"16","author":[{"given":"Nika","family":"Mazej Jeram","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Jo\u017eef Stefan Institute, Jamova cesta 39, 1000 Ljubljana, Slovenia"},{"name":"Faculty of Pharmacy, University of Ljubljana, A\u0161ker\u010deva cesta 7, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1040-5365","authenticated-orcid":false,"given":"Emanuela","family":"Senjor","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Jo\u017eef Stefan Institute, Jamova cesta 39, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4228-3518","authenticated-orcid":false,"given":"Janko","family":"Kos","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Jo\u017eef Stefan Institute, Jamova cesta 39, 1000 Ljubljana, Slovenia"},{"name":"Faculty of Pharmacy, University of Ljubljana, A\u0161ker\u010deva cesta 7, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2314-2733","authenticated-orcid":false,"given":"Milica","family":"Peri\u0161i\u0107 Nanut","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Jo\u017eef Stefan Institute, Jamova cesta 39, 1000 Ljubljana, Slovenia"},{"name":"Faculty of Pharmacy, University of Ljubljana, A\u0161ker\u010deva cesta 7, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.semcancer.2024.09.002","article-title":"Unravelling the Complexities of Resistance Mechanism in Pancreatic Cancer: Insights from in Vitro and Ex-Vivo Model Systems","volume":"106\u2013107","author":"Lencioni","year":"2024","journal-title":"Semin. 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