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 and Haijun Yu ()
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Mengxue Zhou: Chinese Academy of Sciences
Jiaxin Wang: Chinese Academy of Sciences
Jiaxing Pan: Chinese Academy of Sciences
Hui Wang: Inner Mongolia University
Lujia Huang: Chinese Academy of Sciences
Bo Hou: Chinese Academy of Sciences
Yi Lai: Chinese Academy of Sciences
Fengyang Wang: Tongji University School of Medicine
Qingxiang Guan: Jilin University
Feng Wang: Fudan University
Zhiai Xu: East China Normal University
Haijun Yu: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39035-x

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