Nanovesicles loaded with a TGF-β receptor 1 inhibitor overcome immune resistance to potentiate cancer immunotherapy.
Mengxue ZhouJiaxin WangJiaxing PanHui WangLujia HuangBo HouYi LaiFengyang WangQingxiang GuanFeng WangZhiai XuHaijun YuPublished in: Nature communications (2023)
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.
Keyphrases
- transforming growth factor
- photodynamic therapy
- magnetic resonance
- epithelial mesenchymal transition
- drug delivery
- cancer therapy
- fluorescence imaging
- magnetic resonance imaging
- poor prognosis
- binding protein
- type diabetes
- squamous cell carcinoma
- mesenchymal stem cells
- wastewater treatment
- high resolution
- small molecule
- metabolic syndrome
- amino acid
- contrast enhanced
- signaling pathway
- wound healing
- single molecule