{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:46:26Z","timestamp":1793040386794,"version":"4.5.0"},"reference-count":81,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to critically review the current evidence on the anticancer potential of the cell-derived secretome, with emphasis on mesenchymal stem\/stromal cell (MSC) products, and to provide a realistic translational roadmap.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This narrative review analyzes preclinical studies (\n                      <jats:italic>in vitro<\/jats:italic>\n                      ) published from 2000 until September 30, 2025, identified through PubMed\/MEDLINE, Scopus, Web of Science, and Google Scholar. We focused on the secretome composition, its source-dependent variability, the reported antitumor mechanisms, and the factors responsible for the conflicting pro-\n                      <jats:italic>versus<\/jats:italic>\n                      anti-tumorigenic outcomes. This narrative review covers the literature from January 2000 up to December 1, 2025 (final search: PubMed\/MEDLINE, Scopus, Web of Science, ClinicalTrials.gov; terms: \u201csecretome\u201d OR \u201cexosome\u201d AND \u201ccancer\u201d AND \u201cclinical trial\u201d).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key findings<\/jats:title>\n                    <jats:p>\n                      Numerous preclinical studies demonstrate that certain MSC-derived secretomes\u2014particularly inflammatory-primed, serum-free preparations from perinatal tissues (Wharton\u2019s jelly or umbilical cord) and extracellular vesicle (EV)-depleted or genetically\/drug-loaded variants\u2014consistently reduce the cancer cell viability, migration, angiogenesis, and tumor growth (55%\u201385% inhibition in rodent models) across breast, prostate, lung, glioma, and melanoma models. Conversely, unprimed adult tissue MSC secretomes and intact exosome fractions frequently exert neutral or tumor-promoting effects. Engineered platforms (e.g., TRAIL- or azurin-expressing MSCs and paclitaxel-primed amniotic cells) achieve the largest potency gains (from 10- to 100-fold) and favorable safety profiles\n                      <jats:italic>in vivo<\/jats:italic>\n                      . To date, no clinical trial has reported on the anticancer efficacy of any cell-free secretome product in humans.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Translational implications<\/jats:title>\n                    <jats:p>Clinical advancement requires immediate consensus on an optimal perinatal-sourced candidate, mandatory priming\/EV depletion, validated quantitative potency assays, and Good Manufacturing Practice (GMP)-compliant manufacturing. With coordinated effort, first-in-human phase I trials could commence by 2028\u20132029, offering a novel, off-the-shelf paracrine therapy for solid tumors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1729022","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T05:41:42Z","timestamp":1772602902000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Cell secretome as a potential anticancer therapeutic agent: composition, mechanisms, preclinical evidence, and translational challenges"],"prefix":"10.3389","volume":"16","author":[{"given":"Noor","family":"Alrushaid","sequence":"first","affiliation":[{"name":"Department of Stem Cell Biology, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University","place":["Dammam, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naif A.","family":"AlQurashi","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University","place":["Dammam, Saudi Arabia"]},{"name":"Department of Basic Sciences, Deanship of Preparatory Year and Supporting Studies, Imam Abdulrahman Bin Faisal University","place":["Dammam, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bayan Saeed","family":"Alobaidi","sequence":"additional","affiliation":[{"name":"Indepedent Volunteer","place":["Dammam, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firdos Alam","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University","place":["Dammam, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.200900514","article-title":"Plant secretome: Unlocking secrets of the secreted proteins","volume":"10","author":"Agrawal","year":"2010","journal-title":"Proteomics"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/vco.12779","article-title":"Visualizing the cancer stem-like properties of canine tumour cells with low proteasome activity","volume":"20","author":"Sung","year":"2022","journal-title":"Vet Comp Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/cells13110982","article-title":"Tigilanol Tiglate-Induced Changes in Secretome Profiles Alter C-Met Phosphorylation and Cell Surface Protein Expression in H357 Head and Neck Cancer Cells","volume":"13","author":"Antwi","year":"2024","journal-title":"Cells"},{"key":"B4","article-title":"Study on knowledge of chemotherapy\u2019s adverse effects and their self-care ability to manage - The cancer survivors impact","volume":"11","author":"Arunachalam","year":"2021","journal-title":"Clin Epidemiol Glob Health"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.44923","article-title":"Trends in Prices of Drugs Used to Treat Metastatic Non-Small Cell Lung Cancer in the US from 2015 to 2020","author":"Desai","year":"2022","journal-title":"JAMA Netw. 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