Nature Communications
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2021
·Vol. 12
·期 1
·1-20
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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
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免疫疗法
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药学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
CANCER CELL
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2022
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IF 38.585
Haixia Long,Qingzhu Jia,Liuyang Wang,Wenfeng Fang,Zhongyu Wang,Tao Jiang,Fei Zhou,Zheng Jin,Jiani Huang,Li Zhou,Chunyan Hu,Xinxin Wang,Jin Zhang,Yujie Ba,Yujie Gong,Xianghua Zeng,Dong Zeng,Xingxing Su,Peter B. Alexander,Li Wang,Limei Wang,Yisong Y. Wan,Xiao-Fan Wang,Li Zhang,Qi-Jing Li,Bo Zhu
Summary Despite the unprecedented success of immune checkpoint inhibitors (ICIs) as anti-cancer therapy, it remains a prevailing clinical need to identify additional mechanisms underlying ICI therapeutic efficacy and potential drug resistance. Here, using lineage tracking in cancer patients and tumor-bearing mice, we demonstrate that erythroid progenitor cells lose their developmental potential and switch to the myeloid lineage. Single-cell transcriptome analyses reveal that, notwithstanding quantitative differences in erythroid gene expression, erythroid differentiated myeloid cells (EDMCs) are transcriptionally indistinguishable from their myeloid-originated counterparts. EDMCs possess multifaceted machinery to curtail T cell-mediated anti-tumor responses. Consequently, EDMC content within tumor tissues is negatively associated with T cell inflammation for the majority of solid cancers; moreover, EDMC enrichment, in accordance with anemia manifestation, is predictive of poor prognosis in various cohorts of patients undergoing ICI therapy. Together, our findings reveal a feedforward mechanism by which tumors exploit anemia-triggered erythropoiesis for myeloid transdifferentiation and immunosuppression.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症治疗
✓ 已验证
DOI
PubMed
高影响因子
CANCER RESEARCH
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2025
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IF 16.6
Zhang Jie,Chen Weiwu,Zhang Chen,He Qian,Wang Xudong,Han Jiayu,Gao Peng,Wang Kunyu,Xie Haoze,Gao Feng,Guo Yining,Guo Wenhao,Jiang Haofei,Le Jing,Zang Ruichen,Mo Sisi,Fan Haobo,Zhu Xiaoxiao,Jiang Xinrong,Gao Fengbin,Yu Yanlan,Ding Guoqing,Chen Yicheng
PD-1 restrains effective killing of cancer cells by the immune system and is predominantly located on the surface of T cells or other immune cells. However, cancer cells also express PD-1 to varying degrees, which is commonly associated with a poor prognosis. Here, we investigated the regulation and function of PD-1 expression in prostate cancer (PCa) and revealed the impact on the tumor microenvironment. PD-1 expression in cancer cells positively correlated with Gleason grade and metastasis but negatively correlated with CD8+ T cell infiltration in PCa patients. PCa cells secreted PD-1 in exosomes that enhanced the activity of myeloid-derived suppressor cells (MDSCs) by activating JAK/STAT3 signaling. The activated MDSCs in turn reduced the infiltration of CD8+ T cells within the tumor, promoting tumor immune evasion. The ubiquitin-specific protease USP7 induced deubiquitination and elevated the abundance of PD-1 in PCa, and USP7 inhibition sensitized PCa tumors to anti-PD-1 antibody treatment. Given the modest efficacy of current immunotherapeutic approaches for PCa, strategies to inhibit the secretion of PD-1-bearing exosomes or USP7 function may emerge as promising immunostimulatory interventions for treating PCa.
研究领域:
癌症生物学
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免疫学
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分子生物学
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细胞信号传导
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泌尿学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
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2019
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IF 13.903
Weidong Nie,Wei Wei,Liping Zuo,Chengliang Lv,Fan Zhang,Gui-Hong Lu,Feng Li,Guanghao Wu,Li−Li Huang,Xiaobo Xi,Hai-Yan Xie
Although adoptive T-cell therapy has been successful in hematological malignancy treatment, its application in solid tumors remains a great challenge. Here, using a pH-sensitive benzoic–imine bond and inverse electron-demand Diels–Alder cycloaddition, we prepared magnetic nanoclusters (NCs) armed with responsive PD-1 antibody (aP), which could then bind onto effector T cells due to their PD-1 expression. After adoptive transfer, the magnetization and superparamagnetism of NCs enabled us to magnetically recruit effector T cells and aP simultaneously to tumor sites with MRI guidance. Owing to the acidic intratumoral microenvironment, the benzoic–imine bond then hydrolyzed, leading to the release of aP. The therapeutic effects of adoptive T cells and free aP could thus be spatiotemporally coupled. As a result, we achieved inhibition of tumor growth with few side effects, demonstrating the great promise of such a chemical approach for safe and high-performance adoptive T-cell therapy against solid tumors.
研究领域:
癌症免疫治疗
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纳米技术
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生物医学工程
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-20
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IF 10.6
Guo Hong,Li Xia,Mao Dengxuan,Wang Hong,Wei Liangyin,Qu Ding,Qin Xiaoying,Li Xiaoqi,Liu Yuping,Chen Yan
The insufficient abundance and weak activity of tumour-infiltrating lymphocytes (TILs) are two important reasons for the poor efficacy of PD-1 inhibitors in hepatocellular carcinoma (HCC) treatment. The combined administration of tanshinone II A (TSA) and astragaloside IV (As) can up-regulate the abundance and activity of TILs by normalising tumour blood vessels and reducing the levels of immunosuppressive factors respectively. For enhancing the efficacy of PD-1 antibody, a magnetic metal–organic framework (MOF) with a homologous tumour cell membrane (Hm) coating (Hm@TSA/As-MOF) is established to co-deliver TSA&As into the HCC microenvironment. Hm@TSA/As-MOF is a spherical nanoparticle and has a high total drug-loading capacity of 16.13 wt%. The Hm coating and magnetic responsiveness of Hm@TSA/As-MOF provide a homologous-magnetic dual-targeting, which enable Hm@TSA/As-MOF to counteract the interference posed by ascites tumour cells and enhance the precision of targeting solid tumours. Hm coating also enable Hm@TSA/As-MOF to evade immune clearance by macrophages. The release of TSA&As from Hm@TSA/As-MOF can be accelerated by HCC microenvironment, thereby up-regulating the abundance and activity of TILs to synergistic PD-1 antibody against HCC. This study presents a nanoplatform to improve the efficacy of PD-1 inhibitors in HCC, providing a novel approach for anti-tumour immunotherapy in clinical practice.
研究领域:
肿瘤学
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药学
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生物医学工程
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2025
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IF 19
Qi Chen,Yue Zhou,Xudong Zhu,Lei Xu,Ge Bai,Yaru Zhou,Nannan Zhang,Hongwen Liu,Yani Pan,Yu Liu,Lishan Wang,Xueni Fu,Jingjing Wei,Lina Zhou,Lu Xu,Yuxiang Sun,Zhangding Wang,Shanshan Shen,Yun Zhu,Lei Wang
Tumor-associated neutrophils (TANs), particularly the N2 phenotype, contribute to T cell exhaustion in cholangiocarcinoma (CCA), leading to low response rates to PD-1 inhibitor therapy. To address this issue, cancer-associated fibroblast (CAF)-derived extracellular vesicles loaded with ruxolitinib (CEVs@Ru) are developed to selectively target and reprogram N2 TANs, thereby modulating the immunosuppressive tumor microenvironment (TME). The combination of CEVs@Ru with anti-PD-1 antibody therapy significantly enhanced antitumor efficacy, reducing tumor weight by 89.86% and normalizing liver weight, without significant adverse effects. This approach improved the local concentration of ruxolitinib, increased CD8+ T cell infiltration, and reduced regulatory T cells, indicating a remodeled TME conducive to effective antitumor immunity. The findings provide a promising strategy for enhancing PD-1 inhibitor efficacy and improving patient outcomes in CCA and potentially other solid tumors.
研究领域:
肿瘤学
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免疫学
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药理学
✓ 已验证
产品关联
DOI
高影响因子
Acta Biomaterialia
·
2023
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IF 9.7
Bo Li,Tong Yang,Jin Liu,Xixi Yu,Xinying Li,Fei Qin,Jiefei Zheng,Jinxia Liang,Youyan Zeng,Zhenhua Zhou,Lu Liu,Bin Zhang,Weiwei Yao,Zhuo Feng,Guandi Zeng,Qian Zhou,Liang Chen
Non-small cell lung cancer (NSCLC) remains the most frequently diagnosed lung cancer and the leading cause of cancer-related mortality worldwide. PD-1/PD-L1 axis inhibitors have changed the treatment paradigm for various cancer types, including NSCLC. However, success of these inhibitors in lung cancer clinic is severely limited by their inability to inhibit the PD-1/PD-L1 signaling axis due to heavy glycosylation and heterogeneity expression of PD-L1 in NSCLC tumor tissue. Taking advantage of the facts that tumor cell derived nanovesicles could efficiently accumulate in the homotypic tumor sites due to their innate targeting abilities and that specific and high affinity existed between PD-1 and PD-L1, we developed NSCLC targeting biomimetic nanovesicles (NV) cargos from genetically engineered NSCLC cell lines that overexpressed PD-1 (P-NV). We showed that P-NVs efficiently bound NSCLC cells in vitro and targeted tumor nodules in vivo . We further loaded P-NVs with 2-deoxy-D-glucose (2-DG) and doxorubicin (DOX), and found that these drugs co-loaded P-NVs efficiently shrank lung cancers in mouse models for both allograft and autochthonous tumor. Mechanistically, drug-loaded P-NVs efficiently caused cytotoxicity to tumor cells and simultaneously activated anti-tumor immunity function of tumor-infiltrating T cells. Our data therefore strongly argue that 2-DG and DOX co-loaded, PD-1-displaying nanovesicles is a highly promising therapy for treatment of NSCLC in clinic. Statement of significance Lung cancer cells overexpressing PD-1 are developed for preparing nanoparticles (P-NV). PD-1s displayed on NVs enhance their homologous targeting abilities to tumor cells expressing PD-L1s. Chemotherapeutics such as DOX and 2-DG, are packaged in such nanovesicles (PDG-NV). These nanovesicles efficiently delivered chemotherapeutics to tumor nodules specifically. The synergy between DOX and 2-DG is observed in inhibiting lung cancer cells in vitro and in vivo . Importantly, 2-DG causes deglycosylation and downregulation of PD-L1 on tumor cells while PD-1 displayed on nanovesicles’ membrane blocks PD-L1 on tumor cells. 2-DG loaded nanoparticles thus activate anti-tumor activities of T cells in the tumor microenvironment. Our work thus highlights the promising antitumor activity of PDG-NVs, which warrants further clinical evaluation.
研究领域:
肿瘤学
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药学
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生物技术
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2024
·Vol. 43
·期 1
·1-22
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IF 11.4
Tu Xiaoxuan,Chen Longxian,Zheng Yi,Mu Chenglin,Zhang Zhiwei,Wang Feiyu,Ren Yiqing,Duan Yingxin,Zhang Hangyu,Tong Zhou,Liu Lulu,Sun Xunqi,Zhao Peng,Wang Lie,Feng Xinhua,Fang Weijia,Liu Xia
Background The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers capable of prognosticating efficacy in HCC patients who are poised to receive anti-PD-1 monotherapy within the phase III clinical trial, KEYNOTE394. Additionally, we sought to elucidate the underlying molecular mechanisms for resistance to immune checkpoint blockade (ICB) and propose innovative combination immunotherapy strategies for future clinical application.Methods Patient blood samples were collected for single-cell RNA sequencing to evaluate the immune cell signature before receiving ICB therapy. Subsequently, in vitro assays and in vivo murine model experiments were conducted to validate the mechanism that S100A9+CD14+ monocytes play a role in ICB resistance.Results Our study demonstrates a notable enrichment of S100A9+CD14+ monocytes in the peripheral blood of patients exhibiting suboptimal responses to anti-PD-1 therapy. Moreover, we identified the Mono_S100A9 signature as a predictive biomarker, indicative of reduced efficacy in immunotherapy and decreased survival benefits across various tumor types. Mechanistically, S100A9 activates PD-L1 transcription by directly binding to the CD274 (PD-L1) gene promoter, thereby suppressing T-cell proliferation and cytotoxicity via the PD-1/PD-L1 axis, consequently diminishing the therapeutic effectiveness of subsequent anti-PD-1 treatments. Furthermore, our in vivo studies revealed that inhibiting S100A9 can synergistically enhance the efficacy of anti-PD-1 drugs in the eradication of hepatocellular carcinoma.Conclusion sOur study underscores the significance of S100A9+CD14+ monocytes in predicting inadequate response to ICB treatment and provides insights into the monocyte cell-intrinsic mechanisms of resistance to ICB therapy. We also propose a combined therapeutic approach to enhance ICB efficacy by targeting S100A9.
研究领域:
肿瘤学
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免疫学
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分子生物学
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临床试验
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2022
·
IF 15.304
Yu-Xiang Ge,Tai-Wei Zhang,Lei Zhou,Wang Ding,Hai-Feng Liang,Zhi-Chao Hu,Qin Chen,Jian Dong,Feng-Feng Xue,Xiao-Fan Yin,Li-Bo Jiang
Poor immunogenicity and compromised T cell infiltration impede the application of immune-checkpoint blockade (ICB) immunotherapy for osteosarcoma (OS). Although autophagy is involved in enhancing the immune response, the synergistic role of autophagy in ICB immunotherapy and the accurate control of autophagy levels in OS remain elusive and challenging. Here, we designed a pH-sensitive autophagy-controlling nanocarrier, [email protected] @PEG-FA (CBZP), loading a natural derivative, curcumin (CUR), to boost the immunotherapeutic response of PD-1/PD-L1 blockade by activating immunogenic cell death (ICD) via autophagic cell death, and BMS1166 to inhibit the PD-1/PD-L1 interaction simultaneously, enhancing the tumor immunogenicity and sensitizing the antitumor T cell immunity. After entering tumor cells, the pH-sensitive nanoparticles induced autophagy and decreased the intracellular pH , which in turn further facilitated the release of CUR to enhance autophagic activity. Transferring CBZP to orthotopic OS tumor-bearing mice showed powerful antitumor effects and established long-term immunity against tumor recurrence, accompanied by enhanced dendritic cell maturation and tumor infiltration of CD8 + T lymphocytes. Collectively, CBZP exhibited synergistic effects in treating OS by combining ICD induction with checkpoint blockade, thereby shedding light on the use of autophagy control as a potential clinical therapy for OS.
研究领域:
肿瘤学
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免疫疗法
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纳米技术
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药理学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2023
·Vol. 21
·期 1
·1-22
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IF 10.2
Zhang Shushan,Huang Yongquan,Pi Songying,Chen Hui,Ye Feile,Wu Chaoqun,Li Liujun,Ye Qing,Lin Yuhong,Su Zhongzhen
Incomplete radiofrequency ablation (IRFA) triggers mild protective autophagy in residual tumor cells and results in an immunosuppressive microenvironment. This accelerates the recurrence of residual tumors and causes resistance to anti-PD-1/PDL1 therapy, which bringing a great clinical challenge in residual tumors immunotherapy. Mild autophagy activation can promote cancer cell survival while further amplification of autophagy contributes to immunogenic cell death (ICD). To this regard, we constructed active targeting zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) loaded with STF62247 or both STF62247 and BMS202, namely STF62247@ZIF-8/PEG-FA (SZP) or STF62247-BMS202@ZIF-8/PEG-FA (SBZP) NPs. We found that SZP NPs inhibited proliferation and stimulated apoptosis of residual tumor cells exposed to sublethal heat stress in an autophagy-dependent manner. Further results discovered that SZP NPs could amplify autophagy in residual tumor cells and evoke their ICD, which dramatically boosted the maturation of dendritic cells (DCs). Through vaccination experiments, we found for the first time that vaccination with heat + SZP treatment could efficiently suppress the growth of new tumors and establish long-term immunological memory. Furthermore, SBZP NPs could remarkably promote the ICD of residual tumor cells, obviously activate the anti-tumor immune microenvironment, and significantly inhibit the growth of residual tumors. Thus, amplified autophagy coupled with anti-PD-1/PDL1 therapy is potentially a novel strategy for treating residual tumors after IRFA.Graphical Abstract
研究领域:
肿瘤学
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免疫治疗
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纳米技术
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癌症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2023
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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
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免疫学
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癌症研究
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
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IF 6.6
Haishui Sun,Xiao Wang,Zhaoyang Guo,Zhenrong Hu,Yuanchen Yin,Shuhan Duan,Wenwen Jia,Wei Lu,Jingzhou Hu
Introduction Traditional surgical resection, radiotherapy, and chemotherapy have been the treatment options for patients with head and neck squamous cell carcinoma (HNSCC) over the past few decades. Nevertheless, the five-year survival rate for patients has remained essentially unchanged, and research into treatments has been relatively stagnant. The combined application of photothermal therapy (PTT) and immunotherapy for treating HNSCC has considerable potential.Methods Live-dead cell staining and CCK-8 assays proved that Fe3O4 nanoparticles are biocompatible in vitro. In vitro, cellular experiments utilized flow cytometry and immunofluorescence staining to verify the effect of Fe3O4 nanoparticles on the polarisation of tumor-associated macrophages. In vivo, animal experiments were conducted to assess the inhibitory effect of Fe3O4 nanoparticles on tumor proliferation under the photothermal effect in conjunction with BMS-1. Tumour tissue sections were stained to observe the effects of apoptosis and the inhibition of tumor cell proliferation. The histological damage to animal organs was analyzed by hematoxylin and eosin (H&E) staining.Results The stable photothermal properties of Fe3O4 nanoparticles were validated by in vitro cellular and in vivo animal experiments. Fe3O4 photothermal action not only directly triggered immunogenic cell death (ICD) and enhanced the immunogenicity of the tumor microenvironment but also regulated the expression of tumor-associated macrophages (TAMs), up-regulating CD86 and down-regulating CD206 to inhibit tumor growth. The PD-1/PD-L1 inhibitor promoted tumor suppression, and reduced tumor recurrence and metastasis. In vivo studies demonstrated that the photothermal action exhibited a synergistic effect when combined with immunotherapy, resulting in significant suppression of primary tumors and an extension of survival.Conclusion In this study, we applied Fe3O4 photothermolysis in a biomedical context, combining photothermolysis with immunotherapy, exploring a novel pathway for treating HNSCC and providing a new strategy for effectively treating HNSCC.
研究领域:
癌症生物学
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纳米技术
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免疫疗法
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生物医学工程
✓ 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）