{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T23:22:36Z","timestamp":1790464956598,"version":"4.1.0"},"reference-count":249,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"NHMRC MRFF","doi-asserted-by":"publisher","award":["2027365"],"award-info":[{"award-number":["2027365"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005627","name":"Thrasher Research Fund","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100005627","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Elaine Henry Fellowship"},{"name":"Griffith University Postdoctoral Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The lysosome is no longer viewed as a simple degradative \u201ctrash can\u201d of the cell. The lysosome is not only degradative; its acidic, redox-active lumen also serves as a chemical \u201cmicroreactor\u201d that can modulate anticancer drug disposition and activation. This review examines how the distinctive chemical features of the lysosome, including its acidic pH (~4.5\u20135), strong redox gradients, limited thiol-reducing capacity, generation of reactive oxygen (ROS), diverse acid hydrolases, and reservoirs of metal ions, converge to influence the fate and activity of anticancer drugs. The acidic lumen promotes sequestration of weak-base drugs, which can reduce efficacy by trapping agents within a protective \u201csafe house,\u201d yet can also be harnessed for pH-responsive drug release. Lysosomal redox chemistry, driven by intralysosomal iron and copper, catalyzes Fenton-type ROS generation that contributes to oxidative damage and ferroptosis. The lysosome\u2019s broad enzyme repertoire enables selective prodrug activation, such as through protease-cleavable linkers in antibody\u2013drug conjugates, while its membrane transporters, particularly P-glycoprotein (Pgp), can sequester chemotherapies and promote multidrug resistance. Emerging therapeutic strategies exploit these processes by designing lysosomotropic drug conjugates, pH- and redox-sensitive delivery systems, and combinations that trigger lysosomal membrane permeabilization (LMP) to release trapped drugs. Acridine\u2013thiosemicarbazone hybrids exemplify this approach by combining lysosomal accumulation with metal-based redox activity to overcome Pgp-mediated resistance. Advances in chemical biology, including fluorescent probes for pH, redox state, metals, and enzymes, are providing new insights into lysosomal function. Reframing the lysosome as a chemical reactor rather than a passive recycling compartment opens new opportunities to manipulate subcellular pharmacokinetics, improve drug targeting, and overcome therapeutic resistance in cancer. Overall, this review translates the chemical principles of the lysosome into design rules for next-generation, more selective anticancer strategies.<\/jats:p>","DOI":"10.3390\/ijms262311581","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T08:13:49Z","timestamp":1764576829000},"page":"11581","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Lysosome as a Chemical Reactor"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8430-827X","authenticated-orcid":false,"given":"Mahendiran","family":"Dharmasivam","sequence":"first","affiliation":[{"name":"Institute for Biomedicine and Glycomics, Griffith University, Gold Coast, QLD 4215, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2706-172X","authenticated-orcid":false,"given":"Busra","family":"Kaya","sequence":"additional","affiliation":[{"name":"Institute for Biomedicine and Glycomics, Griffith University, Gold Coast, QLD 4215, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Xiang, Y., Li, N., Liu, M., Chen, Q., Long, X., Yang, Y., Xiao, Z., Huang, J., Wang, X., and Yang, Y. 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