Nano Research
·
2021
·Vol. 15
·期 1
·510-518
·
IF 8.897
Wu Jia-Si,Li Jia-Xian,Shu Na,Duan Qi-Jia,Tong Qi-Song,Zhang Jing-Yang,Huang Yong-Cong,Yang Si-Yu,Zhao Zhi-Bin,Du Jin-Zhi
Tumor associated macrophages (TAMs) tend to exhibit tumor-promoting M2 phenotype and contribute to the development of immunosuppressive microenvironment of solid tumors. Reprograming TAMs from M2 into tumoricidal M1 phenotype is robust for stimulating tumor immunosuppressive microenvironment (TIME). In this study, we developed a poly(amidoamine) (PAMAM) derivative dendrimer (denoted as fourth generation- N,N -diethylaminoethyl (G4-DEEA)) for efficient loading of Toll-like receptor 7 and 8 (TLR7/8) agonist (R848) to remodel the TIME for potent cancer immunotherapy. G4-DEEA exhibited a high loading capacity of R848 up to 35.9 wt% by taking advantage of its dendritic structure. The resulting formulation (designated as G4-DEEA@R848) effectively polarized M2 macrophages into M1 phenotype in vitro , and improved the maturation and activation of antigen-presenting cells. In the 4T1 orthotopic breast cancer model, G4-DEEA@R848 showed a stronger tumor inhibitory effect than free drug. The mechanistic studies suggested that G4-DEEA@R848 could significantly stimulate the TIME by repolarizing TAMs into M1 phenotype, reducing the presence of immunosuppressive myeloid cells and increasing the infiltration of tumor cytotoxic T cells. This study provides a simple but effective dendrimer-based strategy to improve the formulation of R848 for improved cancer immunotherapy.
研究领域:
癌症免疫治疗
·
药学
·
免疫学
✓ 已验证
产品关联
DOI
高影响因子
IMMUNITY
·
2024
·
IF 25.5
Zhigang Nian,Yingchao Dou,Yiqing Shen,Jintang Liu,Xianghui Du,Yong Jiang,Yonggang Zhou,Binqing Fu,Rui Sun,Xiaohu Zheng,Zhigang Tian,Haiming Wei
As the most frequent genetic alteration in cancer, more than half of human cancers have p53 mutations that cause transcriptional inactivation. However, how p53 modulates the immune landscape to create a niche for immune escape remains elusive. We found that cancer stem cells (CSCs) established an interleukin-34 (IL-34)-orchestrated niche to promote tumorigenesis in p53-inactivated liver cancer. Mechanistically, we discovered that Il34 is a gene transcriptionally repressed by p53, and p53 loss resulted in IL-34 secretion by CSCs. IL-34 induced CD36-mediated elevations in fatty acid oxidative metabolism to drive M2-like polarization of foam-like tumor-associated macrophages (TAMs). These IL-34-orchestrated TAMs suppressed CD8 + T cell-mediated antitumor immunity to promote immune escape. Blockade of the IL-34-CD36 axis elicited antitumor immunity and synergized with anti-PD-1 immunotherapy, leading to a complete response. Our findings reveal the underlying mechanism of p53 modulation of the tumor immune microenvironment and provide a potential target for immunotherapy of cancer with p53 inactivation.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Xiaoyou Zhang,Zichen Yang,Hui Zhi,Shiyu Chen,Weimin Yin,Lulu An,Rongjie Li,Yanni Cai,Caoyi You,Haiqing Dong,Yongyong Li,Yan Li
Tumor-associated macrophages (TAMs) play a crucial role in tumor progression and therapy resistance. The mechanochemical synergy has emerged as a key mechanism regulating the polarization of TAMs toward the tumor-promoting M2 phenotype. However, whether this synergy can be exploited to reprogram TAMs to a tumor-suppressive M1 phenotype remains an unexplored therapeutic strategy. Here, we report a mechanochemically synergistic nanoplatform, RMSN@EXO, designed to reprogram TAMs efficiently and enhance the anti-tumor immune microenvironment. This nanoplatform is composed of mesoporous silica nanoparticles (MSNs) with tailored elasticity and is loaded with the immunomodulator resiquimod (R848). Both MSNs and R848 were identified through screening based on the M1-specific metabolic marker, lactate. And RMSN is subsequently encapsulated within exosomes derived from M1 macrophage. Surprisingly, this nanoplatform efficiently reprograms TAMs into a pro-inflammatory M1-phenotype more effectively than either R848 or MSNs alone. Benefiting from the superior penetration of mechanically tailored MSNs in the TME and the exosome-mediated tumor targeting, RMSN@EXO exhibits enhanced accumulation in hypoxic regions of solid tumors. In vivo experiments further show that repolarized TAMs in hypoxic areas have a significant inhibitory effect on tumor growth. In conclusion, this study establishes a “nano-mechanochemical synergy” strategy to efficiently reprogram TAMs to enhance robust anti-tumor immunity. It provides a fundamental framework for designing nanomedicines based on mechanical properties to improve cancer immunotherapy.
研究领域:
纳米医学
·
免疫治疗
·
癌症生物学
·
生物工程
·
材料科学
·
生物力学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2020
·Vol. 16
·期 38
·2003543
·
IF 11.459
Lingqiao Liu,Yi Wang,Xing Guo,Jingya Zhao,Shaobing Zhou
The progress of antitumor immunotherapy is usually limited by tumor-associated macrophages (TAMs) that account for the highest proportion of immunosuppressive cells in the tumor microenvironment, and the TAMs can also be reversed by modulating the M2-like phenotype. Herein, a biomimetic polymer magnetic nanocarrier is developed with selectively targeting and polarizing TAMs for potentiating immunotherapy of breast cancer. This nanocarrier PLGA-ION-R837 @ M (PIR @ M) is achieved, first, by the fabrication of magnetic polymer nanoparticles (NPs) encapsulating Fe 3 O 4 NPs and Toll-like receptor 7 (TLR7) agonist imiquimod (R837) and, second, by the coating of the lipopolysaccharide (LPS)- treated macrophage membranes on the surface of the NPs for targeting TAMs. The intracellular uptake of the PIR @ M can greatly polarize TAMs from M2 to antitumor M1 phenotype with the synergy of Fe 3 O 4 NPs and R837. The relevant mechanism of the polarization is deeply studied through analyzing the mRNA expression of the signaling pathways. Different from previous reports, the polarization is ascribed to the fact that Fe 3 O 4 NPs mainly activate the IRF5 signaling pathway via iron ions instead of the reactive oxygen species-induced NF-κB signaling pathway. The anticancer effect can be effectively enhanced through potentiating immunotherapy by the polarization of the TAMs in the combination of Fe 3 O 4 NPs and R837.
研究领域:
纳米技术
·
癌症免疫学
·
生物医学工程
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2022
·
IF 10.633
Kai Sun,Jiaying Yu,Jinzhong Hu,Jian Chen,Jia Song,Zhixin Chen,Zhuoer Cai,Zhuoxuan Lu,Liming Zhang,Zhifei Wang
The delivery of salicylic acid or its derivatives to tumor tissue in the form of nanomedicine is critical for the studies on their potential synergistic mechanism in tumor therapy and chemoprevention considering the dangerous bleeding in the high-dose oral administration. To deepen the understanding of their role in adjusting immunosuppressive tumor microenvironment (ITM), herein, we firstly developed a hypoxia-sensitive Fe-5,5′-azosalicylic acid nanoscale coordination polymer nanomedicines (FeNCPs) via a “old drugs new tricks” strategy for synergistic chemodynamic therapy (CDT) and remodulation of ITM to elevate antitumor immunotherapy effect. PEGylated FeNCPs could be reductively cleaved to release 5-aminosalicylic acid (5-ASA) and ferric ions by azo-reductase under hypoxic conditions, which could induce tumor cell death by Fenton reaction-catalysis enhanced CDT and 5-ASA-converted carboxylquinone to promote the production of •OH. Meanwhile, cyclooxygenase-2 (COX-2) and its enzymatic product prostaglandin E 2 (PGE 2 ), as immune negative regulatory molecules, can promote tumor progression and immune tolerance . The released 5-ASA as a COX inhibitor could suppress the expression of PGE 2 , and Fe 3+ was employed to reeducate M2-like tumor-associated macrophages (TAMs) to M1-like phenotype, which could initiate antitumor immune response to reach better antitumor immunotherapy. This work broadens the application of salicylic acid derivatives in antitumor immunotherapy, and provides a new strategy for their “old drugs new tricks”. Statement of Significance Cyclooxygenase-2 (COX-2) and its enzymatic product prostaglandin E2 (PGE 2 ), as immune negative regulatory molecules, facilitate the differentiation of immune cells into immunosuppressive cells to build the immunosuppressive tumor microenvironment, which can promote tumor progression and immune tolerance. Thus, down-regulation of COX-2/PGE 2 expression may be a key approach to tumor treatments. Meanwhile, as a class of inhibitors of COX-2/PGE 2 , the potential mechanism of aspirin or 5-aminosalicylic acid has been a mystery in tumor therapy and chemoprevention. To expand the application of aspirin family nanomedicine in biomedicine , herein, we firstly developed a hypoxia-sensitive Fe-5,5′-azosalicylic acid nanoscale coordination polymer nanomedicines via a “old drugs new tricks” strategy for synergistic chemodynamic therapy and remodulation of immunosuppressive tumor microenvironment to elevate antitumor immunotherapy effect.
研究领域:
肿瘤学
·
药学
·
免疫学
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2022
·
IF 18.027
Xilin Li,Jingmei Pan,Yan Li,Funeng Xu,Jianwen Hou,Guang Yang,Shaobing Zhou
How to precisely reprogram tumor-associated macrophages (TAMs) and combine them with immunogenic cell death (ICD) is still a great challenge in enhancing the antitumor immunotherapeutic effect. Here, we developed a localized drug delivery system with a step-by-step cell internalization ability based on a hierarchical-structured fiber device. The chemotherapeutic agent-loaded nanomicelles are encapsulated in the internal chambers of the fiber, which could first be internalized by actively targeting tumor cells to induce ICD. Next, the rod-like microparticles can be gradually formed from long to short shape through hydrolysis of the fiber matrix in the tumor microenvironment and selectively phagocytosed by TAMs but not to tumor cells when the length becomes less than 3 μm. The toll-like receptors 7 (TLR7) agonist imiquimod could be released from these microparticles in the cytoplasm to reprogram M2-like TAMs. The in vivo results exhibit that this localized system can synergistically induce an antitumor immune response and achieve an excellent antitumor efficiency. Therefore, this system will provide a promising treatment platform for cancer immunotherapy.
研究领域:
癌症研究
·
药学
·
免疫治疗
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yun Liu,Ziying Zhang,Yu Xia,Mengnan Ran,Qing Wang,Quanxin Wu,Wenhua Yu,Cao Li,Shiying Li,Ning Guo
In addition to tumor cells, M2-like tumor-associated macrophages (TAMs) also promote tumor progression. Accordingly, the strategy of targeted depletion or repolarization of M2-like TAMs becomes attractive. Here, we report a dual-targeting nanoagent SAMMH to tumor cells and M2-like TAMs for combinatorial tumor treatment. After co-loading the sonosensitizer spafloxacin (SPX) and oxidative phosphorylation inhibitor atavaquone (ATO) into hollow MnO 2 , the addition of Fe 3+ and tannic acid-immobilized hyaluronic acid (HA) caused the formation of SAMMH through generating metal-polyphenol networks (MPNs) coatings outside. In vitro endocytosis assays demonstrated the efficient internalization of SAMMH by both tumor cells and M2-like TAMs through the specific CD44-HA interactions. The GSH-sensitive degradation of SAMMH results in the continuous release of SPX and ATO. Meanwhile, SAMMH could catalyze the endogenous H 2 O 2 to extra O 2 , thus improving the therapeutic effect via the combination of Mn 2+ -induced CDT and O 2 -generation/O 2 -economy dual-enhanced sonodynamic therapy (SDT). Interestingly, SAMMH had a good targeted M2-like TAMs depleting capacity and could promote M2-to-M1 TAMs transformation by CDT-enhanced SDT, leading to a combinational anti-tumor effect. This dual-targeting nanoagent is a promising candidate to achieve CDT-enhanced SDT against both tumor cells and M2-like TAMs, thus providing new insights for the development of highly effective antitumor therapeutics.
研究领域:
癌症治疗
·
纳米医学
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Qingxu Song,Gongde Lan,Qian Li,Yang Lin,Xin Chen,Hong Liu,Yufeng Cheng,Yuxia Luan
Hypofractionated radiotherapy (HRT) is a promising approach for tumor treatment, owing to its straightforward elimination of tumor cells and stimulation of immunogenic cell death. However, clinical application of HRT is hindered by the inherent radio-resistance and inadequate immune activation. Herein, an injectable hydrogel platform was reported, enabling a cascade amplification of radiosensitization and immune activation to potentiate HRT. The hydrogel with encapsulated TLR7/8 agonist R848 is in situ constructed in tumor via L-norvaline-based polymer (LNP, a gelator). During HRT, the released L-norvaline from LNP suppresses L-arginine consumption through arginase 1 (ARG1) pathway, sparing adequate L-arginine that was used for radiosensitizer nitric oxide (NO) production by inducible NO synthase (iNOS). Meanwhile, R848 repolarizes tumor-associated macrophages (TAMs) from M2 type with rich ARG1 to M1 type with rich iNOS, reinforcing NO production and disrupting M2-type TAMs-induced radio-resistance and immunosuppression. Therefore, the hydrogel demonstrates a cascade regulation of radio-sensitization and immune activation, achieving powerful inhibition of tumor growth and tumor metastasis. This hydrogel provides a novel approach to potentiate HRT, holding great promise in clinical application.
研究领域:
肿瘤学
·
放射肿瘤学
·
免疫疗法
✓ 已验证
产品关联
DOI
高影响因子
Small
·
2024
·
IF 13
Jiao Chang,Weimin Yin,Hui Zhi,Shiyu Chen,Jiuyuan Sun,Yuge Zhao,Li Huang,Liangyi Xue,Xiaoyou Zhang,Tingting Zhang,Haiqing Dong,Yongyong Li
Cuproptosis is an emerging programmed cell death, displaying great potential in cancer treatment. However, intracellular copper content to induce cuproptosis is unmet, which mainly ascribes to the intracellular pumping out equilibrium mechanism by copper exporter ATP7A and ATP7B. Therefore, it is necessary to break such export balance mechanisms for desired cuproptosis. Mediated by diethyldithiocarbamate (DTC) coordination, herein a strategy to efficiently assemble copper ions into polydopamine nanostructure (PDA-DTC/Cu) for reprogramming copper metabolism of tumor is developed. The deposited Cu 2+ can effectively trigger the aggregation of lipoylated proteins to induce cuproptosis of tumor cells. Beyond elevating intracellular copper accumulation, PDA-DTC/Cu enables to break the balance of copper metabolism by disrupting mitochondrial function and restricting the adenosine triphosphate (ATP) energy supply, thus catalytically inhibiting the expressions of ATP7A and ATP7B of tumor cells to enhance cuproptosis. Meanwhile, the killed tumor cells can induce immunogenic cell death (ICD) to stimulate the immune response. Besides, PDA-DTC/Cu NPs can promote the repolarization of tumor-associated macrophages (TAMs ) to relieve the tumor immunosuppressive microenvironment (TIME). Collectively, PDA-DTC/Cu presented a promising “one stone two birds” strategy to realize copper accumulation and inhibit copper export simultaneously to enhance cuproptosis for 4T1 murine breast cancer immunotherapy.
研究领域:
癌症生物学
·
纳米技术
·
免疫治疗
·
细胞生物学
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2020
·
IF 14.588
Ke Li,Chuanchuan Lin,Ye He,Lu Lu,Kun Xu,Bailong Tao,Zengzilu Xia,Rui Zeng,Yulan Mao,Zhong Luo,Kaiyong Cai
As an increased product of high-rate aerobic glycolysis in tumors, lactate could regulate the immunosuppressive tumor microenvironment (TME). A PEG-CDM surface modified, GSH-dependent responsive hollow mesoporous organosilica nanoplatform loaded with hydroxycamptothecin (HCPT) and siMCT-4 was administrated for synergistic tumor chemo-immunotherapy. The nanoplatform cascaded responded to the weak acid TME and the high level of GSH in tumor cells. HCPT and siMCT-4 were continuously released from the nanoplatform for chemotherapy and inhibiting intracellular lactate efflux. The increased intracellular lactate and HCPT effectively induced tumor cell apoptosis. Moreover, the decreased extracellular lactate polarized tumor-associated macrophages (TAMs) phenotype from M2 type to M1 type and restored CD8+ T cell activity in vivo. The results demonstrated that the nanoplatform effectively removed the immunosuppressive TME, inhibited tumor growth, and suppressed lung metastasis of B16F10 cells and 4T1 cells via the combination of inhibiting lactate efflux and chemotherapy. Accordingly, it suggested a strategy to transform immunosuppressive tumors into “hot” tumors and inhibit the tumor growth with high efficiency in vivo.
研究领域:
纳米技术
·
肿瘤学
·
药学
·
免疫治疗
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2021
·Vol. 12
·期 1
·1-20
·
IF 14.919
Wei Zhaohan,Zhang Xiaoqiong,Yong Tuying,Bie Nana,Zhan Guiting,Li Xin,Liang Qingle,Li Jianye,Yu Jingjing,Huang Gang,Yan Yuchen,Zhang Zelong,Zhang Bixiang,Gan Lu,Huang Bo,Yang Xiangliang
The main challenges for programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) checkpoint blockade lie in a lack of sufficient T cell infiltration, tumor immunosuppressive microenvironment, and the inadequate tumor accumulation and penetration of anti-PD-1/PD-L1 antibody. Resetting tumor-associated macrophages (TAMs) is a promising strategy to enhance T-cell antitumor immunity and ameliorate tumor immunosuppression. Here, mannose-modified macrophage-derived microparticles (Man-MPs) loading metformin (Met@Man-MPs) are developed to efficiently target to M2-like TAMs to repolarize into M1-like phenotype. Met@Man-MPs-reset TAMs remodel the tumor immune microenvironment by increasing the recruitment of CD8 + T cells into tumor tissues and decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells. More importantly, the collagen-degrading capacity of Man-MPs contributes to the infiltration of CD8 + T cells into tumor interiors and enhances tumor accumulation and penetration of anti-PD-1 antibody. These unique features of Met@Man-MPs contribute to boost anti-PD-1 antibody therapy, improving anticancer efficacy and long-term memory immunity after combination treatment. Our results support Met@Man-MPs as a potential drug to improve tumor resistance to anti-PD-1 therapy.
研究领域:
肿瘤学
·
免疫疗法
·
药学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Wenjing Mo,Shujie Liu,Xiaozhi Zhao,Fayun Wei,Yuhang Li,Xinan Sheng,Wenmin Cao,Meng Ding,Wenlong Zhang,Xiaoqing Chen,Longxiyu Meng,Sheng Yao,Wenli Diao,Hui Wei,Hongqian Guo
Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), two immunosuppressive myeloid components within the tumor microenvironment (TME), represent fundamental barriers in cancer immunotherapy, whereas current nanomedicines rarely exert dual modulatory roles on these cell types simultaneously. Reactive oxygen species (ROS) not only mediates MDSC-induced immunosuppression but also triggers differentiation and polarization of M2-TAMs. Herein, an ROS scavenging nanozyme, Zr-CeO, with enhanced superoxide dismutase- and catalase-like activities for renal tumor growth inhibition is reported. Mechanistically, intracellular ROS scavenging by Zr-CeO significantly attenuates MDSC immunosuppression via dampening the unfolded protein response, hinders M2-TAM polarization through the ERK and STAT3 pathways, but barely affects neoplastic cells and cancer-associated fibroblasts. Furthermore, Zr-CeO enhances the antitumor effect of PD-1 inhibition in murine renal and breast tumor models, accompanied with substantially decreased MDSC recruitment and reprogrammed phenotype of TAMs in the tumor mass. Upon cell isolation, reversed immunosuppressive phenotypes of MDSCs and TAMs are identified. In addition, Zr-CeO alone or combination therapy enhances T lymphocyte infiltration and IFN- γ production within the TME. Collectively, a promising strategy to impair the quantity and function of immunosuppressive myeloid cells and sensitize immunotherapy in both renal and breast cancers is provided.
研究领域:
癌症免疫治疗
·
纳米医学
·
免疫学
·
肿瘤微环境
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）