Insights into the mechanism of action of phosphoantigen prodrugs on Vγ9Vδ2 T cell activation

Sharif, Maria, Pinna, Claudia M. A., Rakhimova, Kamila, Taher, Taher E., Beggs, Andrew D., Mehellou, Youcef ORCID: https://orcid.org/0000-0001-5720-8513 and Willcox, Benjamin E. 2026. Insights into the mechanism of action of phosphoantigen prodrugs on Vγ9Vδ2 T cell activation. ACS pharmacology & translational science 9 (9) , pp. 2585-2594. 10.1021/acsptsci.6c00264

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Abstract

The activation of Vγ9Vδ2 T cells has emerged as a promising modality in cancer immunotherapy. Phosphate and phosphonate prodrugs of Vγ9Vδ2 T cell phosphoantigens have been developed as potent activators of Vγ9Vδ2 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 Vγ9Vδ2 T cell activator, zoledronate. Interestingly, these prodrugs, termed HMBP ProPAgens, induced an enhanced and more universal Vγ9Vδ2 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Pharmacy
Publisher:	American Chemical Society
ISSN:	2575-9108
Funders:	Wellcome Trust, MRC
Projects:	099266/Z/12/Z, 200983/Z/16/Z, 221725/Z/20/Z, 514079, 519638
Date of First Compliant Deposit:	4 September 2026
Date of Acceptance:	27 July 2026
Last Modified:	02 Oct 2026 13:08
URI:	https://orca.cardiff.ac.uk/id/eprint/189398

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