Oncolytic Peptide-Nanoplatform Drives Oncoimmune Response and Reverses Adenosine-Induced Immunosuppressive Tumor Microenvironment

Adv Healthc Mater. 2024 Oct;13(26):e2303445. doi: 10.1002/adhm.202303445. Epub 2024 Jul 9.

Abstract

The application of oncolytic peptides has become a powerful approach to induce complete and long-lasting remission in multiple types of carcinomas, as affirmed by the appearance of tumor-associated antigens and adenosine triphosphate (ATP) in large quantities, which jumpstarts the cancer-immunity cycle. However, the ATP breakdown product adenosine is a significant contributor to forming the immunosuppressive tumor microenvironment, which substantially weakens peptide-driven oncolytic immunotherapy. In this study, a lipid-coated micelle (CA@TLM) loaded with a stapled oncolytic peptide (PalAno) and an adenosine 2A receptor (A2AR) inhibitor (CPI-444) is devised to enact tumor-targeted oncolytic immunotherapy and to overcome adenosine-mediated immune suppression simultaneously. The CA@TLM micelle accumulates in tumors with high efficiency, and the acidic tumor microenvironment prompts the rapid release of PalAno and CPI-444. Subsequently, PalAno induces swift membrane lysis of tumor cells and the release of antigenic materials. Meanwhile, CPI-444 blocks the activation of the immunosuppressive adenosine-A2AR signaling pathway. This combined approach exhibits pronounced synergy at stalling tumor growth and metastasis in animal models for triple-negative breast cancer and melanoma, providing a novel strategy for enhanced oncolytic immunotherapy.

Keywords: adenosine; adenosine 2A receptor inhibitor; adenosine triphosphate; immunogenic cell death; immunotherapy; oncolytic peptide.

MeSH terms

  • Adenosine* / chemistry
  • Animals
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunotherapy / methods
  • Mice
  • Micelles
  • Peptides / chemistry
  • Receptor, Adenosine A2A / metabolism
  • Tumor Microenvironment* / drug effects

Substances

  • Adenosine
  • Receptor, Adenosine A2A
  • Peptides
  • Micelles