期刊
ADVANCED SCIENCE
卷 9, 期 23, 页码 -出版社
WILEY
DOI: 10.1002/advs.202201271
关键词
hydrogel; sustained drug release; TNBC; UCB-NK cell therapy; wound healing
资金
- National Natural Science Foundation of China [81770651, 81770648, 82172585, 81870449]
- China Postdoctoral Science Foundation [2020M672984]
- Guangzhou Science and Technology Program Key RD Program [202206010072]
The study demonstrates that suberoylanilide hydroxamic acid (SAHA) and 3-methyl adenine (3MA) can be used to enhance umbilical cord blood-based natural killer (UCB-NK) cell therapy for triple-negative breast cancer (TNBC). An injectable hydrogel is designed to codeliver SAHA and 3MA and exhibits excellent anti-relapse efficacy and hemostasis and wound-healing functions.
Triple-negative breast cancer (TNBC) exhibits resistance to conventional treatments due to the presence of cancer stem cells (CSCs), causing postsurgical relapse and a dismal prognosis. Umbilical cord blood natural killer (UCB-NK) cell-based immunotherapy represents a promising strategy for cancer treatment. However, its therapeutic efficacy is greatly restrained by downregulation of the NK cell activation ligand MHC class I-related chain A/B (MICA/B) and autophagy-mediated degradation of NK cell-derived granzyme B (GZMB) in CSCs. Herein, it is demonstrated that suberoylanilide hydroxamic acid (SAHA) epigenetically downregulates let-7e-5p and miR-615-3p to increase MICA/B expression and that 3-methyl adenine (3MA) inhibits autophagy-mediated GZMB degradation, thereby sensitizing breast CSCs to UCB-NK cells. Then, an injectable hydrogel is designed to codeliver SAHA and 3MA to enhance UCB-NK cell infusion efficacy in TNBC. The hydrogel precursors can be smoothly injected into the tumor resection bed and form a stable gel in situ, allowing for a pH-sensitive sustained release of SAHA and 3MA. Moreover, UCB-NK cell infusion in combination with the hydrogel efficiently controls postsurgical relapse of TNBC. In addition, the hydrogel exhibits good hemostasis and wound-healing functions. Therefore, the work provides proof of concept that an injectable epigenetic autophagic modulatory hydrogel augments UCB-NK cell therapy to combat postsurgical relapse of TNBC.
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