Potentiating cancer immunotherapies with modular albumin-hitchhiking nanobody–STING agonist conjugates
The enhancement of antitumour immunity via agonists of the stimulator of interferon genes (STING) pathway is limited by pharmacological barriers. Here we show that the covalent conjugation of a STING agonist to anti-albumin nanobodies via site-selective bioconjugation chemistries prolongs the circulation of the agonist in the blood and increases its accumulation in tumour tissue, stimulating innate immune programmes that increased the infiltration of activated natural killer cells and T cells, which potently inhibited the growth of mouse tumours. The technology is modular, as demonstrated by the recombinant integration of a second nanobody domain targeting programmed death-ligand 1 (PD-L1), which further increased the accumulation of the agonist in tumours while blocking immunosuppressive PD-1/PD-L1 interactions. The bivalent nanobody-STING agonist conjugate stimulated robust antigen-specific T-cell responses and long-lasting immunological memory and conferred enhanced therapeutic efficacy. It was also effective as a neoadjuvant treatment to adoptive T-cell therapy. As a modular approach, hitchhiking STING agonists on serum albumin may serve as a broadly applicable strategy for augmenting the potency of systemically administered cancer immunotherapies.
Authors
- Jody C. May (ORCID: https://orcid.org/0000-0003-4871-5024)
- Lucinda E. Pastora (ORCID: https://orcid.org/0009-0006-2409-6360)
- Ann Hanna (ORCID: https://orcid.org/0000-0003-2734-6426)
- Vijaya Bharti (ORCID: https://orcid.org/0000-0002-0970-6988)
- Ann Richmond (ORCID: https://orcid.org/0000-0002-9580-900X)
- Payton T. Stone (ORCID: https://orcid.org/0000-0002-8105-0610)
- Taylor L. Sheehy (ORCID: https://orcid.org/0000-0002-3100-8115)
- Emily N. Arner (ORCID: https://orcid.org/0000-0003-3589-8829)
- JOHN A. JUN. MCLEAN (ORCID: https://orcid.org/0000-0001-8918-6419)
- Neil C. Chada (ORCID: https://orcid.org/0000-0003-4566-3564)
- Alexander J. Kwiatkowski (ORCID: https://orcid.org/0000-0001-5435-3555)
- John T. Wilson (ORCID: https://orcid.org/0000-0002-9144-2634)
- Lauren Hubert (ORCID: https://orcid.org/0009-0007-6268-0362)
- Jeffrey C. Rathmell (ORCID: https://orcid.org/0000-0002-4106-3396)
- Joel Finkelstein
- Karan Arora (ORCID: https://orcid.org/0000-0003-1472-1637)
- Barbara Fingleton (ORCID: https://orcid.org/0000-0003-1132-0782)
- Brandie C. Taylor (ORCID: https://orcid.org/0000-0002-4862-4678)
- Katherine N. Gibson‐Corley (ORCID: https://orcid.org/0000-0002-1846-1580)
- W. Kimryn Rathmell (ORCID: https://orcid.org/0000-0002-4984-0225)
- Blaise R. Kimmel (ORCID: https://orcid.org/0000-0002-9582-9887)
- Ebony Hargrove-Wiley (ORCID: https://orcid.org/0000-0003-4452-4917)
- Justin Micah Balko (ORCID: https://orcid.org/0000-0002-4263-5974)
- Hayden M. Pagendarm (ORCID: https://orcid.org/0000-0001-7611-6120)
- Jinming Yang (ORCID: https://orcid.org/0000-0002-8703-0493)
Institutions
- Vanderbilt University (US)
- VA Tennessee Valley Healthcare System (US)
- Virginia Innovation Partnership Corporation (US)
- Vanderbilt Health (US)
- The Ohio State University (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Nature Biomedical Engineering
- Published
- 2025-06-11
- DOI
- https://doi.org/10.1038/s41551-025-01400-0
- Citations
- 37
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 29.51
Funders
- National Science Foundation
- U.S. Department of Veterans Affairs
- Pharmaceutical Research and Manufacturers of America Foundation
- Susan G. Komen
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases
- Congressionally Directed Medical Research Programs