Advanced Science
·
2022
·Vol. 9
·期 23
·2201271
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IF 17.521
Yihang Gong,Wenjie Chen,Xiuxing Chen,Yizhan He,Hua Jiang,Xijian Zhang,Lijie Pan,Beibei Ni,Fan Yang,Yan Xu,Qi Zhang,Lei Zhou,Yusheng Cheng
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.
研究领域:
肿瘤学
·
免疫治疗
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2021
·
IF 12.479
Jiankun Guan,Yuxin Wu,Xin Liu,Huimin Wang,Ningbing Ye,Zheng Li,Chen Xiao,Zhijie Zhang,Zifu Li,Xiangliang Yang
Cancer stem cells (CSCs) present grand challenges for triple-negative breast cancer (TNBC). Conventional chemotherapy drugs, including Camptothecin (CPT), not only cannot eradicate CSCs but also foster a suppressive immune microenvironment for the initiation and proliferation of CSCs. Herein, we report a novel prodrug CPT–SS–NLG919 (CN) and its nanoformulation [email protected] ( [email protected] ), which potently suppress CSCs by regulating CSCs niche in murine TNBC 4T1 tumors. Via inducing immunogenic cell death (ICD) and simultaneous inhibiting indoleamine 2, 3-dioxygenase (IDO), CN and [email protected] promote DC maturation, decrease Treg cells, mitigate tryptophan consumption, and reduce the amount of IL-6, IL-13, and TGF-β, converting CSCs niche to a hostile condition for CSCs to live in and eliminating CSCs efficiently, thereby inducing efficient tumor inhibition in 4T1 tumor models. Our work represents a new paradigm of eliminating CSCs by regulating tumor immune microenvironment and suggests that CN and its nanoformulation [email protected] are promising candidates for the treatment of intractable TNBC.
研究领域:
肿瘤学
·
药理学
·
免疫学
·
纳米技术
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Qiyi Feng,Jie Chen,Jinxing Huang,Xiaojie Li,Xinyi Liu,Chunxiu Xiao,Xiuli Zheng,Xuanming Chen,Jue Li,Zhongwei Gu,Kui Luo,Kai Xiao,Weimin Li
Cancer stem cells (CSCs) have been demonstrated to be involved in tumor initiation and relapse, and the presence of CSCs in the tumor tissue often leads to therapeutic failure. BBI608 has been identified to eliminate CSCs by inhibiting signal transducer and activator of transcription 3 (STAT3). In this study, we confirm that BBI608 can efficiently suppress the proliferation and migration of non-small cell lung cancer (NSCLC) cells, and specifically kill the stemness-high population in chemoresistant NSCLC cells. To improve its bioavailability and tumor accumulation, BBI608 is successfully encapsulated into redox-responsive PEGylated branched N-(2-hydroxypropyl) methacrylamide (HPMA)-deoxy cholic acid (DA) polymeric nanoparticles (BBI608-SS-NPs). The BBI608-SS-NPs can release the drug in response to high concentrations of intracellular glutathione, and exhibit cytotoxicity against lung cancer cells and CSCs comparable to the free drug BBI608. Furthermore, the BBI608-SS-NPs preferentially accumulate in tumor sites, resulting in a superior anti-tumor efficacy in both cisplatin-resistant cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of NSCLC. Mechanistic studies demonstrate that BBI608-SS-NPs not only directly inhibit the downstream genes of the STAT3 pathway, but also indirectly inhibit the Wnt pathway. Overall, this stimuli-responsive polymeric nanoformulation of BBI608 shows great potential in the treatment of chemoresistant NSCLC by targeting CSCs.
研究领域:
肿瘤学
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药学
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纳米技术
·
癌症生物学
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2023
·
IF 29.4
Daoxia Guo,Xiaoyuan Ji,Hui Xie,Jia Ma,Chunchen Xu,Yanfeng Zhou,Nan Chen,Hui Wang,Chunhai Fan,Haiyun Song
Cancer-associated fibroblasts (CAFs) promote cancer stem cell (CSC)-mediated chemoresistance and immunosuppressive tumor microenvironment. However, direct depletion of CAFs may increase cancer invasiveness and metastasis. As a generalized strategy against chemoresistant cancers, we design Gemini-like homotypic targeting nanoparticles (NPs) for two-pronged CAF transformation and cancer cell elimination. The CAF-targeted NPs couple vitamin B 3 metabolic reprogramming to epigenetic modulation of secreted pro-stemness and immunosuppressive factors, thereby diminishing CSC and suppressive immune cell populations to enhance cancer cell drug susceptibility and cytotoxic T cell infiltration. In mouse models of breast, liver, pancreatic and colorectal cancers that are resistant to their respective first-line chemotherapeutics, a single dose of hydrogel co-delivering the Gemini-like NPs can rehabilitate chemosensitivity, induce immune activation, and achieve tumor regression. Moreover, it stimulates robust T cell memory for long-term protection against tumor rechallenge. Our study thus represents an innovative approach with broad applicability for overcoming cancer chemoresistance. This article is protected by copyright. All rights reserved
研究领域:
肿瘤学
·
纳米技术
·
免疫疗法
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
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