Nature Communications (Jun 2023)

Nanovesicles loaded with a TGF-β receptor 1 inhibitor overcome immune resistance to potentiate cancer immunotherapy

  • Mengxue Zhou,
  • Jiaxin Wang,
  • Jiaxing Pan,
  • Hui Wang,
  • Lujia Huang,
  • Bo Hou,
  • Yi Lai,
  • Fengyang Wang,
  • Qingxiang Guan,
  • Feng Wang,
  • Zhiai Xu,
  • Haijun Yu

DOI
https://doi.org/10.1038/s41467-023-39035-x
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 18

Abstract

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Abstract The immune-excluded tumors (IETs) show limited response to current immunotherapy due to intrinsic and adaptive immune resistance. In this study, it is identified that inhibition of transforming growth factor-β (TGF-β) receptor 1 can relieve tumor fibrosis, thus facilitating the recruitment of tumor-infiltrating T lymphocytes. Subsequently, a nanovesicle is constructed for tumor-specific co-delivery of a TGF-β inhibitor (LY2157299, LY) and the photosensitizer pyropheophorbide a (PPa). The LY-loaded nanovesicles suppress tumor fibrosis to promote intratumoral infiltration of T lymphocytes. Furthermore, PPa chelated with gadolinium ion is capable of fluorescence, photoacoustic and magnetic resonance triple-modal imaging-guided photodynamic therapy, to induce immunogenic death of tumor cells and elicit antitumor immunity in preclinical cancer models in female mice. These nanovesicles are further armored with a lipophilic prodrug of the bromodomain-containing protein 4 inhibitor (i.e., JQ1) to abolish programmed death ligand 1 expression of tumor cells and overcome adaptive immune resistance. This study may pave the way for nanomedicine-based immunotherapy of the IETs.