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Phosphate and phosphonate prodrugs of V\u03b39V\u03b42 T cell phosphoantigens have been developed as potent activators of V\u03b39V\u03b42 T cells that are capable of effectively facilitating lysis of a range of cancer cells in vitro. In this work, we show that phosphonate prodrugs of the phosphoantigen derivative, HMBP, enter cells in an energy-independent manner and produce their pharmacological activity independently of the mevalonate pathway, a target of the widely used bisphosphonate and V\u03b39V\u03b42 T cell activator, zoledronate. Interestingly, these prodrugs, termed HMBP ProPAgens, induced an enhanced and more universal V\u03b39V\u03b42 T cell cytotoxicity against diverse cancer cell lines in vitro compared to zoledronate, an effect also observed in patient-derived colorectal cancer organoids. Together, the data presented in this work further support the development of HMBP ProPAgens as a novel class of cancer immunotherapeutic agents.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00264","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T11:56:23Z","timestamp":1788436583000},"page":"2585-2594","source":"Crossref","is-referenced-by-count":0,"title":["Insights into the\nMechanism of Action of Phosphoantigen\nProdrugs on V\u03b39V\u03b42 T Cell Activation"],"prefix":"10.1021","volume":"9","author":[{"given":"Maria","family":"Sharif","sequence":"first","affiliation":[{"name":"University of Birmingham , , Edgbaston , ,","place":["Birmingham, U.K., B15 2TT"]},{"name":"University of Birmingham , , Edgbaston , ,","place":["Birmingham, U.K., B15 2TT"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5618-7842","authenticated-orcid":true,"given":"Claudia M. A.","family":"Pinna","sequence":"additional","affiliation":[{"name":"University of Birmingham , , Edgbaston , ,","place":["Birmingham, U.K., B15 2TT"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamila","family":"Rakhimova","sequence":"additional","affiliation":[{"name":"University of Birmingham , , Edgbaston , ,","place":["Birmingham, U.K., B15 2TT"]},{"name":"University Hospitals Birmingham NHS Foundation Trust , ,","place":["Birmingham, U.K., B15 2GW"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taher E.","family":"Taher","sequence":"additional","affiliation":[{"name":"University of Birmingham , , Edgbaston , ,","place":["Birmingham, U.K., B15 2TT"]},{"name":"University of Birmingham , , Edgbaston , ,","place":["Birmingham, U.K., B15 2TT"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"Beggs","sequence":"additional","affiliation":[{"name":"University of Birmingham , , Edgbaston , ,","place":["Birmingham, U.K., B15 2TT"]},{"name":"University Hospitals Birmingham NHS Foundation Trust , ,","place":["Birmingham, U.K., B15 2GW"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5720-8513","authenticated-orcid":true,"given":"Youcef","family":"Mehellou","sequence":"additional","affiliation":[{"name":"Cardiff University , , ,","place":["Cardiff, U.K., CF10 3NB"]},{"name":"Cardiff University , , ,","place":["Cardiff, U.K., CF10 3AT"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6113-2109","authenticated-orcid":true,"given":"Benjamin E.","family":"Willcox","sequence":"additional","affiliation":[{"name":"University of Birmingham , , Edgbaston , ,","place":["Birmingham, U.K., B15 2TT"]},{"name":"University of Birmingham , , Edgbaston , ,","place":["Birmingham, U.K., B15 2TT"]},{"name":"National Institute for Health and Care Research (NIHR) , , ,","place":["Birmingham, U.K., B15 2TH"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"2026091109132497600_cit1","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/j.1600-065X.2006.00479.x","article-title":"Nonpeptide antigens, presentation\nmechanisms, and immunological memory of human V\u03b32V\u03b42 T\ncells: discriminating friend from foe through the recognition of prenyl\npyrophosphate antigens","volume":"215","author":"Morita","year":"2007","journal-title":"Immunol. 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