ACS Nano
·
2023
·
IF 17.1
Jia-Qi Luo,Rong Liu,Fang-Man Chen,Jing-Yang Zhang,Sui-Juan Zheng,Dan Shao,Jin-Zhi Du
Enabling macrophages to phagocytose tumor cells holds great potential for cancer therapy but suffers from tremendous challenges because the tumor cells upregulate antiphagocytosis molecules (such as CD47) on their surface. The blockade of CD47 alone is insufficient to stimulate tumor cell phagocytosis in solid tumors due to the lack of “eat me” signals. Herein, a degradable mesoporous silica nanoparticle (MSN) is reported to simultaneously deliver anti-CD47 antibodies (aCD47) and doxorubicin (DOX) for cancer chemo-immunotherapy. The codelivery nanocarrier aCD47-DMSN was constructed by accommodating DOX within the mesoporous cavity, while adsorbing aCD47 on the surface of MSN. aCD47 blocks the CD47-SIRPα axis to disable the “don’t eat me” signal, while DOX induces immunogenic tumor cell death (ICD) for calreticulin exposure as an “eat me” signal. This design facilitated the phagocytosis of tumor cells by macrophages, which enhanced antigen cross-presentation and elicited efficient T cell-mediated immune response. In 4T1 and B16F10 murine tumor models, aCD47-DMSN generated a strong antitumor effect after intravenous injection by increasing tumor-infiltration of CD8+ T cells. Taken together, this study offers a nanoplatform to modulate the phagocytosis of macrophages for efficacious cancer chemo-immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Zubair Hussain,Shanshan Gou,Xu Liu,Mengyu Li,Hanyue Zhang,Sumei Ren,Ruxia Han,Fangfang Liu,Xiaowen Zhou,Lu Qiu,Hongfei Wang,Zhenzhen Chen,Kangdong Liu
Immunotherapy has significantly advanced cancer treatment, but the tumor immune microenvironment (TIME) often remains immunosuppressive, limiting therapeutic efficacy. Tumor-associated macrophages (TAMs), particularly M2-like macrophages, play a crucial role in promoting tumor growth and immune evasion. Our study introduces a novel approach using dual-targeted ZrMOF/C@P nanoparticles, smartly engineered with cell membrane coating and enzyme responsiveness, to effectively modulate TAMs. These nanoparticles are synthesized and loaded with 2’, 3’-cGAMP, a STING agonist, and encapsulated in a peptide-expressed macrophage membrane (PMM) featuring Pep20, MMP2, and M2pep. In vitro , they activate the STING pathway in M2-like macrophages and reprogram them into M1-like macrophages. Smart ZrMOF/C@P is found to accumulate at the tumor even 72 hours post-injection. In CT26 and 4T1 tumor models show that smart ZrMOF/C@P not only suppresses tumor growth but also stimulates systemic immune responses. This is evidenced by a reduction in M2-like and an increase in M1-like macrophages, enhanced dendritic cell (DC) maturation, and increased tumor infiltration of CD4 + and CD8 + T cells, accompanied by elevated IFN-γ secretion. This innovative use of ZrMOF/C@P offers a promising strategy to transform the immunosuppressive TIME, presenting a versatile and effective treatment option for solid tumors, and novel avenue for non-CDN-STING agonists, facilitating systemic administration.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2024
·
IF 8.7
Qing Xia,Feila Liu,Yue Zhou,Guanyuan Yang,Fangzhou Li,Tingting Liang,Jun Liu,Wanling Li,Yaqing Huang,Chuhong Zhu
The accumulation of foam cells in the subendothelial space of the vascular wall to form plaques is the real cause of atherosclerotic lesions. Conventional interventions, such as statins and anti-cytokine or anti-inflammatory therapies, suffer problems in terms of their short therapeutic outcomes and potential disruption of the immune system. The development of more efficient therapeutics to restrict the initial progression of plaques appears to be crucial for treating and preventing atherosclerosis. Decreasing foam cell formation by reversing the excessive phagocytosis of modified low-density lipoprotein (LDL) in macrophages is highly desirable. Here, we developed a strategy based on engineered monocytes to dynamically regulate lipid uptake by macrophages inspired by a CD47–SIRPα signaling-induced defect in the phagocytosis of lesional macrophages at the advanced stage of AS. Briefly, a complex called CD47p-GQDs-miR223, which is designed to interact with SIRPα, was synthesized to remodel monocytes by decreasing the uptake of oxidized LDL through the activation of CD47-SIRPα signaling. After injection, these monocytes compete for recruitment to atherosclerotic plaques, release gene drugs and mediate anti-inflammatory phenotypic remodeling of the aboriginal macrophages, effectively inhibiting the development of foam cells. Our strategy provides a new therapeutic for preventing the progression of atherosclerosis.
研究领域:
心血管疾病
·
分子生物学
·
治疗学
·
免疫学
✓ 已验证
DOI
高影响因子
ACS Chemical Neuroscience
·
2024
·
IF 4.1
Wei Du,Xiaomin Zhang,Songze Li,Xin Xie
This study aims to investigate the role of neuronal SIRPα and microglial synaptic remodeling in sevoflurane-induced cognitive dysfunction in newborn mice. Newborn mice were exposed to sevoflurane, followed by behavioral assessments and single-cell transcriptome sequencing of cortical cells. Lentivirus-mediated overexpression of neuronal SIRPα and assessment of the microglial morphology and synaptic function were conducted. Sevoflurane exposure resulted in social cognitive impairments without affecting motor coordination. Transcriptomic analysis revealed no significant changes in cortical microglial cells or neurons. However, sevoflurane inhibited nonsynaptic synapse modification by microglia. Overexpression of neuronal SIRPα enhanced microglial function, promoted neuron development, and ameliorated cognitive impairments. SCENIC analysis identified a correlation between IRF8 and SIRPα expression. This study sheds light on the involvement of neuronal SIRPα and microglial synaptic remodeling in sevoflurane-induced cognitive dysfunction. Understanding these mechanisms offers new avenues for exploring cognitive impairment pathways and potential therapeutic targets.
研究领域:
神经科学
·
分子生物学
·
发育生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Yurong Wei,Min Zhao,Tianpei He,Na Chen,Li Rao,Long Chen,Yun Zhang,Yanbing Yang,Quan Yuan
Immunotherapy including immune checkpoint inhibition has reinvigorated the current cancer treatment field. The development of efficient cancer immunotherapies depends on a thorough understanding of the status of immune checkpoints and how they interact. However, the distribution and spatial organization changes of immune checkpoints during their interactions at the single-molecule level remain difficult to directly visualize due to the lack of in situ imaging techniques with appropriate spatial and stoichiometric resolution. Herein, we report the direct visualization and quantification of the spatial distribution and organization of CD47 on the bladder tumor cell membrane and SIRPα on the macrophage membrane by using a single-molecule localization imaging technique called quantitative direct stochastic optical reconstruction microscopy (QdSTORM). Results showed that a portion of CD47 and SIRPα was present on cell membranes as heterogeneous clusters of varying sizes and densities prior to activation. Quantitative analyses of the reconstructed super-resolution images and theoretical simulation revealed that CD47 and SIRPα were reorganized into larger clusters upon binding to each other. Furthermore, we found that blocking the immune checkpoint interaction with small-molecule inhibitors or antibodies significantly impacted the spatial clustering behavior of CD47 on bladder tumor cells, demonstrating the promise of our QdSTORM strategy in elucidating the molecular mechanisms underlying immunotherapy. This work offers a promising strategy to advance our understanding of immune checkpoint state and interactions while also contributing to the fields including signal regulation and cancer therapy.
研究领域:
癌症生物学
·
免疫学
·
显微镜技术
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Xiang Yu,Xiaoyao Hao,Mingjiu Chen,Huricha Baigude
Therapeutic targeting of the CD47-SIRPα axis has emerged as a pivotal strategy for enhancing phagocytic clearance of tumor cells and overcoming immune evasion in solid malignancies, yet clinical outcomes with single-agent checkpoint blockade remain suboptimal due to limited activation of innate immunity and on-target toxicities. Administration of STING agonists is hampered by poor pharmacokinetics and nonspecific toxicity, highlighting the need for cell-selective delivery systems that can orchestrate immune activation and checkpoint inhibition. Herein, we conjugated cGAMP to an anti-SIRPα antibody, aiming to effectively reprogram the tumor immune microenvironment. Systemic administration of anti-SIRPα-cGAMP conjugate significantly inhibited tumor growth in a mouse model of colon adenocarcinoma and improved survival in vivo by simultaneously blocking the CD47-SIRPα “do not eat me” checkpoint and selectively delivering the STING agonist to myeloid cells. These findings suggest that targeted immunostimulatory ADCs may be an effective strategy for overcoming immune resistance in solid tumors.
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR HUMAN REPRODUCTION
·
2022
·Vol. 28
·期 5
·
IF 4.518
Li Jing,Yan Shumin,Li Qiuju,Huang Yufei,Ji Miaomiao,Jiao Xue,Yuan Ming,Wang Guoyun
Peritoneal macrophages play a significant role in the progression of endometriosis (EM), but their functional differentiation is still unclear, and their phagocytic ability is weak. CD47-signal-regulated protein α (SIRPα) and PD-L1-PD-1 are considered immune checkpoints associated with macrophage phagocytosis. A specific blockade of these two pathways had been shown to increase the phagocytic clearance of cancer cells by macrophages in most cancers. We hypothesized that targeting CD47/PD-L1 in EM could improve the phagocytosis of macrophages, thereby delaying the progression of EM. From localization to quantification, from mRNA to protein, we comprehensively evaluated the expression of CD47 and PD-L1 in EM. We demonstrated that the CD47 expression in ectopic endometrium from patients with EM was significantly increased, but PD-L1 was not. We performed direct co-culture experiments of endometrial stromal cells with macrophages in vitro and in vivo to assess whether ectopic endometrial stromal cells escape macrophage phagocytosis through the CD47-SIRPα signaling pathway. The results showed that targeting CD47 increased the phagocytic capacity of macrophages. Interestingly, we also found that the reduction of CD47 expression promoted apoptosis of endometrial stromal cells. In conclusion, these data suggested that targeting CD47 can effectively target ectopic endometrial stromal cells through a dual mechanism of increased phagocytosis of macrophages and induced apoptosis of ectopic endometrial stromal cells. Thus, immunotherapy based on the CD47-SIRPα signaling pathway has some potential in treating EM, but further mechanistic studies are needed to explore more effective and specific antibodies.
研究领域:
免疫学
·
妇科学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Cancer Cell International
·
2026
·
IF 7
Siyi Liu,Lin Liang,Zihua Zhou,Chenyu Zhang,Shan Liao,Qian He,Yan Lei,Juan Xu,Gengqiu Luo,Yanling Li,Yanhong Zhou
As a cell surface glycoprotein, CD90 plays a significant role in the initiation and progression of malignancies such as gastric cancer (GC) by influencing tumor cell proliferation, migration, and angiogenesis. However, its specific role in immune evasion in GC and its potential therapeutic value have not been fully explored. In this study, we report that CD90 is highly expressed in GC tissues and is positively correlated with macrophage immune infiltration. Furthermore, we demonstrate that CD90 can mediate immune evasion in GC by affecting the phagocytic function of tumor-associated macrophages (TAMs). Mechanistically, CD90 functions as a scaffold protein, inhibiting the interaction between IGF2BP2 and TRIM21. This inhibition stabilizes the expression of the m6A methylation reader protein IGF2BP2. Subsequently, IGF2BP2 enhances the mRNA stability of the immune checkpoint molecule CD47 in an m6A-dependent manner, leading to the activation of the CD47/SIRPα axis. Ultimately, by inhibiting the phagocytic function of TAMs, CD90 mediates immune evasion in GC. In summary, our work highlights the critical role of the CD90-IGF2BP2-CD47 axis in immune evasion in GC. This finding is expected to provide significant experimental evidence for elucidating the pathogenesis of GC and discovering potential molecular targets for clinical treatment.
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2026
·
IF 17.3
Jinqiao Zhang,Ting Tong,Chang Cai,Xianzhou Cai,Bicheng Sun,Kexin Wen,Xinran Qu,Qin Fan,Ziliang Dong
Radiotherapy, while effective in tumor treatment, often induces upregulation of CD47 checkpoint expression on malignant cells, activating the CD47-SIRPα “don’t eat me” signaling axis to inhibit macrophage-mediated phagocytosis, thereby promoting immune evasion and ultimately compromising therapeutic efficacy. Herein, a radiosensitizer-loaded biomimetic nanodecoy (p@MVs-Sirpα) is constructed by harnessing genetically engineered macrophage-derived vesicles to enhance tumor radioimmunotherapy. p@MVs-Sirpα displays the high surface expression of signal regulatory protein α (SIRPα), enabling it to selectively bind to CD47, a “don’t eat me” signal overexpressed on tumor cells post radiotherapy, thereby competitively blocking the CD47/SIRPα immune checkpoint and promoting macrophage-mediated phagocytosis. Additionally, the nanodecoy is loaded with the radiosensitizing agent polyoxometalates (POMs), which further enhance the efficacy of radiotherapy by modulating the tumor immune microenvironment. This dual-function strategy not only facilitates the immune clearance of tumor cells but also potentiates radiotherapy-induced antitumor responses. p@MVs-Sirpα effectively inhibits the progression of established tumors in multiple murine models. Moreover, in tumor rechallenge experiments, robust and durable immune memory was observed, indicating long-term protection against tumor relapse. Collectively, this study provides a promising proof-of-concept for employing genetically engineered vesicle-based nanodecoy to disrupt radiation-induced immune escape and augment the therapeutic outcomes of radioimmunotherapy.
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Jinren Liu,Yifei Jiang,Linghui Zhong,Jiajia Lu,Rongrong Li,Yifei Pei,Linyi Tang,Meng Sun,Meng Lv,Xingmin Shi,Fuliang Gong,Xili Wu
Macrophage-mediated tumor clearance is frequently restricted by the immunosuppressive tumor microenvironment. This study investigates the immunomodulatory effects of plasma-activated medium (PAM) on macrophage pro-inflammatory activation and antitumor function. Murine RAW264.7 and primary bone marrow-derived macrophages were treated with PAM generated by a helium atmospheric pressure plasma jet. Phenotypic changes and underlying signaling mechanisms were assessed. Functional enhancements in macrophage recruitment and tumor engulfment were quantified using chemotaxis and 3D confocal co-culture assays with Panc02 pancreatic cancer cells. Results show that PAM promotes macrophage activation by increasing spatial recruitment via pro-inflammatory chemokine secretion and enhancing tumor cell engulfment. Mechanistically, PAM drives this functional shift through hierarchical activation of the TLR4/NF-κB and PI3K/AKT signaling cascades. Furthermore, while hydrogen peroxide alone triggers a compensatory upregulation of the inhibitory SIRPα receptor, the reactive oxygen and nitrogen species (RONS) in PAM bypass this negative feedback to directly downregulate SIRPα. These findings demonstrate that PAM-mediated oxidative modulation effectively suppresses the “don't-eat-me” signal and enhances innate antitumor immunity, providing a potential strategy for cancer immunotherapy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 7
·3147
·
IF 4.6
Rui Chang,Xiaohong Chu,Jibing Zhang,Rongrong Fu,Changshun Feng,Dianlong Jia,Rui Wang,Hui Yan,Guangyong Li,Jun Li
Antitumor immunity is an essential component of cancer therapy and is primarily mediated by the innate immune response, which plays a critical role in initiating and shaping the adaptive immune response. Emerging evidence has identified innate immune checkpoints and pattern recognition receptors, such as CD47 and Toll-like receptor 7 (TLR7), as promising therapeutic targets for cancer treatment. Based on the fusion protein Fc-CV1, which comprises a high-affinity SIRPα variant (CV1), and the Fc fragment of the human IgG1 antibody, we exploited a preparation which coupled Fc-CV1 to imiquimod (TLR7 agonist)-loaded liposomes (CILPs) to actively target CT26. WT syngeneic colon tumor models. In vitro studies revealed that CILPs exhibited superior sustained release properties and cell uptake efficiency compared to free imiquimod. In vivo assays proved that CILPs exhibited more efficient accumulation in tumors, and a more significant tumor suppression effect than the control groups. This immunotherapy preparation possessed the advantages of low doses and low toxicity. These results demonstrated that a combination of immune checkpoint blockade (ICB) therapy and innate immunity agonists, such as the Fc-CV1 and imiquimod-loaded liposome preparation utilized in this study, could represent a highly effective strategy for tumor therapy.Keywords:imiquimod;liposome;Fc-CV1;immunotherapy;colon cancer
研究领域:
肿瘤学
·
免疫学
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Lu Ye,Wei Lv,Weichong He,Shengnan Li,Zhiyi Min,Le Gong,Qi Zhang,Chuanhui Teng,Shanbo Sun,Lingyan Lv,Yi Guo,Hongliang Xin
Infiltrative glioma growth makes surgical excision incomplete, and the residual tumor cells proliferate rapidly. Residual glioma cells evade phagocytosis by macrophages through upregulating anti-phagocytosis molecule CD47, which binds to the signal regulatory protein alpha (SIRPα) of macrophages. Specifically, blocking the CD47-SIRPα pathway is a potential strategy for post-resection glioma treatment. In addition, the anti-CD47 antibody (α-CD47) in combination with temozolomide (TMZ) caused an enhanced pro-phagocytic effect due to the TMZ not only destroying DNA but also inducing endoplasmic reticulum stress response of glioma cells. However, the obstruction of the blood-brain barrier makes systemic combination therapy not ideal for post-resection glioma treatment. Herein, we designed a temperature-sensitive hydrogel system based on a moldable thermosensitive hydroxypropyl chitin (HPCH) copolymer to encapsulate both α-CD47 and TMZ as α-CD47& [email protected] for in situ postoperative cavity administration. Through the in vitro and in vivo evaluations, α-CD47& [email protected] significantly inhibited glioma recurrence post-resection through enhancement of pro-phagocytosis of macrophages, recruitment, and activation of CD8 + T cells and NK cells.
研究领域:
肿瘤学
·
药理学
·
生物医学工程
·
免疫治疗
✓ 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）