Acta Pharmaceutica Sinica B (Jun 2022)

Enzyme-instructed and mitochondria-targeting peptide self-assembly to efficiently induce immunogenic cell death

  • Debin Zheng,
  • Jingfei Liu,
  • Limin Xie,
  • Yuhan Wang,
  • Yinghao Ding,
  • Rong Peng,
  • Min Cui,
  • Ling Wang,
  • Yongjie Zhang,
  • Chunqiu Zhang,
  • Zhimou Yang

Journal volume & issue
Vol. 12, no. 6
pp. 2740 – 2750

Abstract

Read online

Immunogenic cell death (ICD) plays a major role in cancer immunotherapy by stimulating specific T cell responses and restoring the antitumor immune system. However, effective type II ICD inducers without biotoxicity are still very limited. Herein, a tentative drug- or photosensitizer-free strategy was developed by employing enzymatic self-assembly of the peptide F-pY-T to induce mitochondrial oxidative stress in cancer cells. Upon dephosphorylation catalyzed by alkaline phosphatase overexpressed on cancer cells, the peptide F-pY-T self-assembled to form nanoparticles, which were subsequently internalized. These affected the morphology of mitochondria and induced serious reactive oxygen species production, causing the ICD characterized by the release of danger-associated molecular patterns (DAMPs). DAMPs enhanced specific immune responses by promoting the maturation of DCs and the intratumoral infiltration of tumor-specific T cells to eradicate tumor cells. The dramatic immunotherapeutic capacity could be enhanced further by combination therapy of F-pY-T and anti-PD-L1 agents without visible biotoxicity in the main organs. Thus, our results revealed an alternative strategy to induce efficient ICD by physically promoting mitochondrial oxidative stress.

Keywords