Acta Biomaterialia
·
2025
·
IF 9.6
Jiaxuan Li,Kuirong Mao,Xiandi Meng,Jialiang Wang,Mengfei Zhao,Yue Lv,Yanbao Xin,Huating Sun,Yuning Zhang,Yong-Guang Yang,Tianmeng Sun
Tumor-associated macrophages (TAMs) significantly influence the clinical outcomes of immune checkpoint blockade (ICB) therapy. Strategies aimed at reprogramming TAMs from the immunosuppressive M2 phenotype to the pro-inflammatory M1 phenotype hold promise for enhancing ICB efficacy. Lipopolysaccharide (LPS), a potent Toll-like receptor 4 (TLR4) ligand, can reprogram TAMs toward an M1 phenotype. However, the systemic application of LPS is restricted due to its pronounced pro-inflammatory properties, which limit safe dosing in cancer treatment. To address this, thermosensitive hydrogels offer a viable solution by optimizing drug bioavailability and reducing systemic dissemination. In our study, carboxymethyl chitosan (CS) was incorporated into Pluronic F127 to extend the hydrogel's degradation period, facilitating the localized delivery and accumulation of LPS within tumor sites. Peritumoral injection of this hydrogel enhanced the tumor-inhibitory effects of anti-PD-1 antibodies, significantly improving the survival of 4T1 tumor-bearing mice. The GelF127CS-LPS hydrogel also increased the expression of the activation marker on tumor-infiltrating dendritic cells, promoted a higher M1/M2 TAM ratio, and enhanced CD8 + T cell infiltration into tumors—key indicators of T-cell-mediated anti-tumor immunity. Notably, no significant liver or hematological toxicity was observed with GelF127CS-LPS treatment, underscoring its favorable safety profile. These findings demonstrate the potential of GelF127CS-LPS as a TAMs-modulating agent and a promising combinatorial strategy to boost ICB therapy effectiveness. Statement of significance LPS, a potent TLR4 ligand, can reprogram tumor-associated macrophages (TAMs) toward an M1 phenotype, thereby contributing to tumor inhibition. However, its anti-tumor application is constrained by the contradiction between high-dose toxicity and insufficient efficacy at low doses. To address this issue, we developed a thermosensitive hydrogel encapsulating LPS, GelF127CS-LPS, which allows localized LPS release within the tumor area. This hydrogel reprograms TAMs at a picogram level of LPS to achieve a favorable M1/M2 ratio and promotes the activation of T cell-mediated antitumor immunity without observable toxicity. Consequently, when combined with immune checkpoint blockade (ICB), the hydrogel can inhibit tumor growth and improve overall survival. This study provides an effective method for tumor-targeted therapeutic LPS delivery to enhance the efficacy of ICB.
研究领域:
肿瘤学
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免疫疗法
·
药学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Quanjuan Guo,Ailu Yang,Rongrong Zhao,Huajun Zhao,Yongliang Mu,Jian Zhang,Qiuju Han,Yuhang Su
Nimodipine, a calcium antagonist, exert beneficial neurovascular protective effects in clinic. Recently, Calcium channel blockers (CCBs) was reported to protect against liver fibrosis in mice, while the exact effects of Nimodipine on liver injury and hepatic fibrosis remain unclear. In this study, we assessed the effect of nimodipine in Thioacetamide (TAA)-induced liver fibrosis mouse model. Then, the collagen deposition and liver inflammation were assessed by HE straining. Also, the frequency and phenotype of NK cells, CD4 + T and CD8 + T cells and MDSC in liver and spleen were analyzed using flow cytometry. Furthermore, activation and apoptosis of primary Hepatic stellate cells (HSCs) and HSC line LX2 were detected using α-SMA staining and TUNEL assay, respectively. We found that nimodipine administration significantly attenuated liver inflammation and fibrosis. And the increase of the numbers of hepatic NK and NKT cells, a reversed CD4 + /CD8 + T ratio, and reduced the numbers of MDSC were observed after nimodipine treatment. Furthermore, nimodipine administration significantly decreased α-SMA expression in liver tissues, and increased TUNEL staining adjacent to hepatic stellate cells. Nimodipine also reduced the proliferation of LX2, and significantly promoted high level of apoptosis in vitro . Moreover, nimodipine downregulated Bcl-2 and Bcl-xl, simultaneously increased expression of JNK, p-JNK, and Caspase-3. Together, nimodipine mediated suppression of growth and fibrogenesis of HSCs may warrant its potential use in the treatment of liver fibrosis.
研究领域:
药理学
·
免疫学
·
肝病学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MICROBIOLOGICAL RESEARCH
·
2024
·
IF 6.1
Li-Li Zhang,Jia-Ying Xu,Yifei Xing,Pengcheng Wu,Yi-Wen Jin,Wei Wei,Lin Zhao,Jing Yang,Guo-Chong Chen,Li-Qiang Qin
Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy. In this study, we investigated the potential protective effect of Lactobacillus rhamnosus GG (LGG) on radiation-induced intestinal injury and its underlying mechanisms. Mice were assigned to a control group, a 10 Gy total abdominal irradiation (TAI) group, or a group pretreated with 10 8 CFU LGG for three days before TAI. Small intestine and gut microbiota were analyzed 3.5 days post-exposure. LGG intervention improved intestinal structure, reduced jejunal DNA damage, and inhibited the inflammatory cGAS/STING pathway. Furthermore, LGG reduced M1 proinflammatory macrophage and CD8+ T cell infiltration, restoring the balance between Th17 and Treg cells in the inflamed jejunum. LGG also partially restored the gut microbiota. These findings suggest the possible therapeutic radioprotective effect of probiotics LGG in alleviating radiation-induced intestinal injury by maintaining immune homeostasis and reshaping gut microbiota.
研究领域:
放射生物学
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免疫学
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微生物学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR THERAPY
·
2024
·
IF 12.1
Xiaozhen Kang,Yifeng Han,Mengdi Wu,Yuxin Li,Peng Qian,Chuning Xu,Zhengyun Zou,Jie Dong,Jiwu Wei
Tumor necrosis factor (TNF) has been recognized as an immune activation factor in tumor immunotherapy. Our study demonstrated that TNF blockade markedly enhanced the antitumor efficacy of oncolytic adenovirus (AdV) therapy. To minimize systemic side effects, we engineered a recombinant oncolytic AdV encoding a TNF inhibitor (AdV-TNFi) to confine TNF blockade within the tumor microenvironment (TME). AdV-TNFi significantly improved therapeutic outcomes across various solid tumor models, including four murine and two golden hamster cancers. Immune cell profiling identified CD8 + T cells as the primary mediators of AdV-TNFi-induced antitumor effects, rather than CD4 + T or NK cells. Additionally, AdV-TNFi significantly decreased the infiltration of suppressive myeloid-derived immune cells within the TME and promoted long-term antitumor immune surveillance. Further investigation indicated that TNFR2, more than TNFR1, is pertinent to the immunosuppressive TME, with a recombinant AdV-encoding anti-TNFR2 demonstrating comparable antitumor efficacy to AdV-TNFi. Moreover, AdV-TNFi enhanced the antitumor efficacy of gemcitabine and immune checkpoint blockades (ICBs), such as anti-PD-L1 and anti-TIGIT antibodies, in pancreatic carcinoma and the anti-EGFR antibody in colon carcinoma. In conclusion, intratumoral blockade of the TNF/TNFR2 axis using AdV augments cancer immunotherapy efficacy while mitigating the risks associated with systemic TNF or TNFR2 suppression, warranting further clinical investigation.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症治疗
✓ 已验证
DOI
PubMed
高影响因子
BIOMATERIALS
·
2020
·
IF 10.317
Lu Wang,Ye He,Tingting He,Genhua Liu,Chuanchua Lin,Ke Li,Lu Lu,Kaiyong Cai
Toll-like receptor (TLR) agonists are the potent stimulants of innate immune system and hold promises as an adjuvant for anticancer immunotherapy. Unfortunately, most of them are limited by a prompt dissemination, and thus caused “wasted inflammation”. Hence, how to restrict their action radius into lymphoid tissues is of great relevance to enhance their efficacy and concomitantly alleviates the side effects. Here, imiquimod (R837), a TLR 7 agonist, was loaded into mesoporous polydopamine (MPDA) nanocarriers with high efficiency. Moreover, its surface was modified by polyvinyl pyrrolidone (PVP) to enhance their lymphatic drainage ability. These nano-adjuvants have obvious advantages in promoting dendritic cell (DC) maturation in comparison to free R837. Moreover, their transportation and retention ability in proximal lymph nodes (LNs) were also confirmed, by which lymphatic drug exposure can be maximized to a great extent. Consequently, effective DC activation and CD8 + T cell responses were observed as expected by R837 released in draining LNs. This effect was further enhanced by the presence of endogenous tumor antigens from apoptosis debris induced by MPDA-based photothermal effect, and thus led to the growth inhibition of subcutaneous B16 melanomas. The results demonstrated the great potency against melanoma of the designed [email protected] nano-adjuvants by combining photothermal conversion property of MPDA with lymphatic-focused immune-activation.
研究领域:
癌症免疫治疗
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纳米技术
·
药学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Advances
·
2020
·
IF 13.117
Xiaoyu Hong,Xiaofang Zhong,Guangsheng Du,Yingying Hou,Yunting Zhang,Zhirong Zhang,Tao Gong,Ling Zhang,Xun Sun
Subunit vaccines generally proceed through a 4-step in vivo cascade—the DUMP cascade—to generate potent cell-mediated immune responses: (1) drainage to lymph nodes; (2) uptake by dendritic cells (DCs); (3) maturation of DCs; and (4) Presentation of peptide-MHC I complexes to CD8+ T cells. How the physical properties of vaccine carriers such as mesoporous silica nanoparticles (MSNs) influence this cascade is unclear. We fabricated 80-nm MSNs with different pore sizes (7.8 nm, 10.3 nm, and 12.9 nm) and loaded them with ovalbumin antigen. Results demonstrated these MSNs with different pore sizes were equally effective in the first three steps of the DUMP cascade, but those with larger pores showed higher cross-presentation efficiency (step 4). Consistently, large-pore MSNs loaded with B16F10 tumor antigens yielded the strongest antitumor effects. These results demonstrate the promise of our lymph node-targeting large-pore MSNs as vaccine-delivery vehicles for immune activation and cancer vaccination.
研究领域:
纳米技术
·
免疫学
·
疫苗学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2019
·Vol. 7
·期 44
·6924-6933
·
IF 5.047
Pei Liu,Weitao Yang,Lei Shi,Haiyan Zhang,Yan Xu,Peiru Wang,Guolong Zhang,Wei R. Chen,Bingbo Zhang,Xiuli Wang
Phototherapy, particularly photothermal therapy (PTT) and photodynamic therapy (PDT), has become a promising therapeutic technique for the treatment of skin cancers because of its minial invasiveness, high efficacy, and low side effects. Nevertheless, single modality therapy, either PTT or PDT, has limited clinical effectiveness in treating skin cancers. Thus, combined applications of PTT and PDT have been frequently reported; however, PTT and PDT often require their respective photoagents and excitation light sources, resulting in challenges in clinical transformation. In this study, to address these issues, we report the use of biocompatible gold nanoclusters Au25(Capt)18 for the concurrent PTT and PDT treatment of cutaneous squamous cell carcinoma (cSCC) using an 808 nm near-infrared (NIR) laser. Utilizing their high light-thermal conversion efficiency, potent generation of singlet oxygen, and strong photothermal stability, Au25(Capt)18 nanoclusters potentiated a significant proliferation suppression of cSCC XL50 cells in vitro and the inhibition of cSCC tumors on SKH-1 mice in vivo. In particular, under 808 nm light irradiation, the tumor-cell-killing contributions of PTT and PDT were estimated to be 28.86% and 71.14%, respectively, by using an ROS scavenger to quench the PDT effect. Tumor-infiltrating CD4+ T and CD8+ T cells were observed after one course of concurrent PTT and PDT. Preliminary toxicity studies indicated low adverse effects of the Au25(Capt)18 nanoclusters. Through this study, we report the use of a simple nanostructure for simultaneous PTT and PDT applications to effectively kill cSCC and to induce anti-tumor immune responses. Our study could lead to the development of effective photoagents for current, synergistic applications of different phototherapies with targeted immunological responses for the treatment of cancers.
研究领域:
肿瘤学
·
纳米技术
·
光疗
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2019
·Vol. 10
·期 1
·1-16
·
IF 11.878
Li Wei,Yang Jie,Luo Lihua,Jiang Mengshi,Qin Bing,Yin Hang,Zhu Chunqi,Yuan Xiaoling,Zhang Junlei,Luo Zhenyu,Du Yongzhong,Li Qingpo,Lou Yan,Qiu Yunqing,You Jian
Immunogenic cell death (ICD)-associated immunogenicity can be evoked through reactive oxygen species (ROS) produced via endoplasmic reticulum (ER) stress. In this study, we generate a double ER-targeting strategy to realize photodynamic therapy (PDT) photothermal therapy (PTT) immunotherapy. This nanosystem consists of ER-targeting pardaxin (FAL) peptides modified-, indocyanine green (ICG) conjugated- hollow gold nanospheres (FAL-ICG-HAuNS), together with an oxygen-delivering hemoglobin (Hb) liposome (FAL-Hb lipo), designed to reverse hypoxia. Compared with non-targeting nanosystems, the ER-targeting naosystem induces robust ER stress and calreticulin (CRT) exposure on the cell surface under near-infrared (NIR) light irradiation. CRT, a marker for ICD, acts as an ‘eat me’ signal to stimulate the antigen presenting function of dendritic cells. As a result, a series of immunological responses are activated, including CD8 + T cell proliferation and cytotoxic cytokine secretion. In conclusion, ER-targeting PDT-PTT promoted ICD-associated immunotherapy through direct ROS-based ER stress and exhibited enhanced anti-tumour efficacy.
研究领域:
癌症治疗
·
纳米技术
·
免疫学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2023
·Vol. 14
·期 2
·1-11
·
IF 9
Yao Yuan,Feng Suya,Li Xuejiao,Liu Taohua,Ye Shengying,Ma Long,Man Shuli
Litchi chinensis seed, as a valuable by-product of the subtropical fruit litchi ( Litchi chinensis Sonn.), has been confirmed to be rich in procyanidins (LPC). The anticarcinogenic properties of procyanidins has been primarily attributed to their antioxidant and anti-inflammatory activities. However, there is a comparative paucity of information on if and how LPC inhibits colon cancer. Here, LPC significantly inhibited CT26 colon cancer cells proliferation and metastasis in vivo and in vitro. In CT26 lung metastatic mice, the anti-metastatic effect of LPC relied on its regulation of gut microbiota such as increase of Lachnospiraceae UCG-006, Ruminococcus , and their metabolites such as acetic acid, propionic acid and butyric acid. In addition, LPC significantly inhibited CT26 colon cancer cells metastasis through increasing CD8 + cytotoxic T lymphocytes infiltration and decreasing the number of macrophages. Antibiotics treatment demonstrated that the therapeutic effect of LPC depended on the gut microbiota, which regulated T cells immune response. Taken together, LPC had strong inhibitory effects on colon cancer pulmonary metastasis by triggering gut-lung axis to influence the T cells immune response. Our research provides a novel finding for the utilization of procyanidins in the future, that is, supplementing more fruits and vegetables rich in procyanidins is beneficial to the treatment of colon cancer, or it can be used as an adjuvant drug in clinical anti-tumor immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
微生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Chan Jin,Jinbo Li,Xiaoguang Yang,Shuang Zhou,Chang Li,Jiang Yu,Zhaomeng Wang,Dun Wang,Zhonggui He,Yiguo Jiang,Yongjun Wang
Immune checkpoint inhibitors (ICIs) represent a new class of immunotherapy drugs, and are used to relieve immune suppression or enhance the immune response through the blockade of checkpoint ligands or receptors. ICIs have achieved great success in clinical cancer treatment. Monoamine oxidase A (MAOA) is a potent immune checkpoint of immunotherapy. Recently, it has been reported that MAOA inhibitors could enhance CD8 + T cell activity by upregulating 5-HT autocrine pathway in T cells. In this study, we synthesized doxorubicin (DOX) and isoniazid (INH, a MAOA inhibitor) conjugates through a pH sensitive hydrazone bond. Results of the in vivo studies showed that DOX-INH could effectively enhance the activity of CD8 + T cells and perform a synergistic anti-tumor effect with PD-L1 small molecular inhibitor (BMS202). In addition, in an orthotopic 4T1 breast cancer model, it was demonstrated that DOX-INH could inhibit the epithelial-mesenchymal transition process by blocking Shh, IL-6, and TGF-β signaling pathways, thereby inhibiting the growth and metastasis of breast cancer. Thus, a simple and effective small molecule conjugate produced by the combination of a chemotherapy drug and a MAOA inhibitor shows broad prospect in cancer therapy.
研究领域:
癌症免疫治疗
·
肿瘤学
·
药理学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Xin Yang,Wanqiong Li,Shuzhen Li,Shaomeng Chen,Zheng Hu,Zhuoying He,Xueqin Zhu,Xiaoshuang Niu,Xiuman Zhou,Huihao Li,Youmei Xiao,Juan Liu,Xinghua Sui,Guanyu Chen,Yanfeng Gao
Peptide immune checkpoint inhibitors in cancer immunotherapy have attracted great attention recently, but oral delivery of these peptides remains a huge challenge due to the harsh gastrointestinal environment, large molecular size, high hydrophilic, and poor transmembrane permeability. Here, for the first time, a fish oil-based microemulsion was developed for oral delivery of programmed death-1/programmed cell death-ligand 1 (PD-1/PD-L1) blocking model peptide, OPBP-1. The delivery system was characterized, in vitro and in vivo studies were conducted to evaluate its overall implication. As a result, this nutraceutical microemulsion was easily formed without the need of co-surfactants, and it appeared light yellow, transparent, good flowability with a particle size of 152 ± 0.73 nm, with a sustained drug release manner of 56.45 ± 0.36% over 24 h and a great stability within the harsh intestinal environment. It enhanced intestinal drug uptake and transportation over human intestinal epithelial Caco-2 cells, and drastically elevated the oral peptide bioavailability of 4.1-fold higher than that of OPBP-1 solution. Meanwhile, the mechanism of these dietary droplets permeated over the intestinal enterocytic membrane was found via clathrin and caveolae-mediated endocytic pathways. From the in vivo studies, the microemulsion facilitated the infiltration of CD8 + T lymphocytes in tumors, with increased interferon-γ (IFN-γ) secretion. Thus, it manifested a promising immune anti-tumor effect and significantly inhibited the growth of murine colonic carcinoma (CT26). Furthermore, it was found that the fish oil could induce ferroptosis in tumor cells and exhibited synergistic effect with OPBP-1 for cancer immunotherapy. In conclusion, this fish oil-based formulation demonstrated great potential for oral delivery of peptides with its natural property in reactive oxygen species (ROS)-related ferroptosis of tumor cells, which provides a great platform for functional green oral delivery system in cancer immunotherapy.
研究领域:
药剂学
·
免疫学
·
癌症研究
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Yinghao Ding,Xueying Zhu,Jian Wen,Junchao Xiong,Shengyi Zhang,Zhimou Yang,Zhi-Wen Hu
Antigen presentation deficiency restricted by class I major histocompatibility complex (MHC-I) causes low antigenicity and antigen escape in tumors, thereby limiting T-cell immunotherapy outcomes. Here, a combined tumor immunotherapy is developed, in which tumors can present exogenous non-tumor antigens, and adoptively transferred CD8 + T cells specific for these antigens are re-targeted to attack tumors. The approach leverages a cascade-responsive peptide self-assembly to co-deliver suitable antigens and the chemotherapeutic drug camptothecin (CPT) to tumors. As a proof-of-concept, to re-target ovalbumin (OVA)-specific OT-I CD8 + T cells against tumors, PSA (Nap-GFFpYE-ss-Ag) and CPSA (CPT-GFFpYE-ss-Ag) are constructed, containing an OVA-derived epitope OVA 257-264 and/or CPT. The design enables the release of a unique N-terminal extended OVA 257-264 and CPT into the cytosol. As a result, the extended antigen is efficiently presented on the tumor surface by MHC-I, and CPT further enhances this presentation. When combined with adoptively transferred OT-I CD8 + T cells, the approach effectively facilitates CD8 + T cell infiltration and tumor inhibition. Additionally, CPSA treatment sensitizes immune responses to programmed cell death-ligand 1 (PD-L1) blockade, allowing the approach to synergize with an anti-PD-L1 antibody for improved tumor eradication.
研究领域:
肿瘤免疫学
·
纳米医学
·
药物递送系统
·
免疫治疗
·
分子自组装
✓ 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）