A 2D Nanoradiosensitizer Enhances Radiotherapy and Delivers STING Agonists to Potentiate Cancer Immunotherapy

Adv Mater. 2022 Sep;34(39):e2110588. doi: 10.1002/adma.202110588. Epub 2022 Aug 26.

Abstract

Despite potent preclinical antitumor activity, activation of stimulator of interferon genes (STING) has shown modest therapeutic effects in clinical studies. Many STING agonists, including 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), show poor pharmacokinetic properties for sustaining STING activation in tumors and achieving optimal antitumor efficacy. Improved delivery of STING agonists and their effective combination with other treatments are needed to enhance their therapeutic effects. Herein, a 2D nanoplatform, cGAMP/MOL, is reported via conjugating cGAMP to a nanoscale metal-organic layer (MOL) for simultaneous STING activation and radiosensitization. The MOL not only exhibits strong radiosensitization effects for enhanced cancer killing and induction of immunogenic cell death, but also retains cGAMP in tumors for sustained STING activation. Compared to free cGAMP, cGAMP/MOL elicits stronger STING activation and regresses local tumors upon X-ray irradiation. Further combination with an immune checkpoint inhibitor bridges innate and adaptive immune systems by activating the tumor microenvironment to elicit systemic antitumor responses.

Keywords: immunotherapy; metal-organic layers; nanoparticles; radiosensitizers; stimulator of interferon gene agonists.

MeSH terms

  • Humans
  • Immune Checkpoint Inhibitors*
  • Immunotherapy
  • Interferons
  • Membrane Proteins / metabolism
  • Neoplasms* / drug therapy
  • Tumor Microenvironment

Substances

  • Immune Checkpoint Inhibitors
  • Membrane Proteins
  • Interferons