Nanoscale
·
2021
·Vol. 13
·期 30
·12966-12978
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IF 7.79
Jie Yu,Xidong He,Zigui Wang,Yupeng Wang,Sha Liu,Xiaoyuan Li,Yubin Huang
Immune checkpoint blockade (ICB) therapy in combination with immunogenic death (ICD) triggered by photothermal therapy (PTT) and oxaliplatin (OXA) treatment was expected to elicit both innate and adaptive immune responses for tumor control and metastasis prevention. In this study, a photothermal agent (IR780), a folic acid (FA) linked oxaliplatin (OXA) prodrug, and PD-L1 inhibitors (BMS-1) were integrated into a liposomal system. The FA tumor-targeting and enhanced permeability and retention (EPR) effect of the liposomal system prolonged circulating times and increased accumulation in tumors, resulting in an enhanced photothermal effect and less systemic toxicity. In addition, PTT and OXA had a considerable synergistic effect in the induction of a combined ICD. The PD-1/PD-L1 checkpoint, which is a negative immune regulatory mechanism, could be blocked by the thermosensitive released BMS-1. Finally, ICD was harnessed to synergize with a small molecule PD-L1 inhibitor for activation of the immune system in the treatment of tumor relapse and metastasis.
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Nano Today
·
2022
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IF 18.962
Di Liu,Hongliang He,Fei Kong,Yixiang Cao,Fengchao Zang,Ming Ma,Ning Gu,Yu Zhang
Currently, multimodal synergistic nanoplatform emerges as an important cancer therapy paradigm, however, multimodal synergistic theranostic nanoplatform remains to be developed. Herein, using the mouse model of breast cancer, a versatile multimodal synergistic theranostic nanoplatform is rationally designed and synthesized for enhancing chemodynamic therapy (CDT), overcoming immunosuppression within tumor microenvironment , and inhibiting metastasis as well as tracking tumor. To fulfill our design, a composite Fe/Mn magnetic nanoparticle is first synthesized by loading with Fe 3 O 4 and BMS-202 (PD-L1 inhibitor) within a poly(lactide-co-glycolide)-based nanoparticle core, which are further modified with in situ synthesis of MnO 2 layer. Then, the composite metal-organic nanoparticle is coated with two targeting moieties hyaluronic acid (HA) and AMD3100 (CXCR4 antagonist), respectively, to achieve the multimodal synergistic theranostic nanoplatform ( [email protected] +AMD). With surface targeting modification, [email protected] +AMD exhibits enhanced tumor accumulation, where it effectively consumes endogenous glutathione to generate Mn 2+ allowing for the enhanced CDT effect, alleviates tumor hypoxia by O 2 generation and reverses the tumor immunosuppression. [email protected] +AMD blocks CXCR4 receptor on cancer cells, thus suppressing the CXCR4-mediated cancer metastasis and invasion. Additionally, [email protected] +AMD would synchronously be achieving tumor tracking by T 1 -T 2 dual-mode magnetic resonance imaging. Collectively, this strategy holds a novel multimodal synergistic theranostics for effective cancer management.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Liyun Zheng,Zhongwei Zhao,Li Chen,Wenjing Yang,Giorgio Ercolani,Pan Qin,Bin Lin,Mengzhu Han,Qiaoyou Weng,Yeyu Zhang,Bin Wu,Minjiang Chen,Zouying Yao,Shiji Fang,Jiansong Ji
Astragalin (ASG), a natural flavonoid glycoside, is known for its multiple pharmacological effects. In this study, we explored the antitumor effects of ASG and its underlying mechanism. Specifically, the growth inhibitory effects of ASG were assessed. Apoptosis rate, reactive oxygen species (ROS) accumulation, mitochondrial damage, and the activation of the endoplasmic reticulum stress induced by ASG were assessed. The potential target of ASG was identified and validated. The effects of ASG on immunogenic cell death (ICD) were determined. Furthermore, ASG’s growth inhibition was validated in vivo , and its potential synergistic effects with anti-PD-L1 antibody were examined. Our findings demonstrate that ASG effectively inhibits growth in liver cancer cell lines. ASG treatment induces apoptosis by promoting mitochondrial membrane potential disruption and ROS accumulation. Additionally, ASG directly bounds to quinone oxidoreductase 2 (NQO2), leading to a reduction in NQO2 protein levels and subsequent upregulation of key ER stress markers, including p-PERK, p-eIF2α, GRP78, and CHOP. Moreover, ASG induces hallmark features of ICD, including calreticulin exposure, nuclear high mobility group box 1 reduction, and adenosine triphosphate release. ASG-treated liver cancer cells effectively enhance dendritic cell maturation in a coculture system. In vivo , the tumor growth is synergistically inhibited by ASG combined with anti-PD-L1 antibody in Hepa1-6 tumor-bearing mice. This synergy is associated with increased dendritic cell maturation, enhanced CD8 + T cell infiltration, and a reduction in regulatory T cells. In conclusion, ASG can be served as a potential anticancer agent for liver cancer and enhance the antitumor efficacy of immunotherapy by activating the ROS-mediated endoplasmic reticulum stress and ICD pathways.
研究领域:
肿瘤学
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药理学
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生物化学
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免疫学
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分子生物学
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细胞生物学
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Science Advances
·
2024
·Vol. 10
·期 40
·
IF 11.7
Feng Zhang,Qiuyu Jiang,Jialiang Cai,Fansheng Meng,Wenqing Tang,Zhiyong Liu,Xiahui Lin,Wenfeng Liu,Yi Zhou,Xizhong Shen,Ruyi Xue,Ling Dong,Si Zhang
The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway in hepatocellular carcinoma (HCC) is limited. NOD-like receptors (NLRs) comprise a highly evolutionarily conserved family of cytosolic bacterial sensors, yet their impact on antitumor immunity against HCC remains unclear. In this study, we uncovered that NOD1, a well-studied member of NLR family, exhibits predominant expression in tumor-associated macrophages (TAMs) and correlates positively with improved prognosis and responses to anti–PD-1 treatments in patients with HCC. Activation of NOD1 in vivo augments antitumor immunity and enhances the effectiveness of anti–PD-1 therapy. Mechanistically, NOD1 activation resulted in diminished expression of perilipin 5, thereby hindering fatty acid oxidation and inducing free fatty acid accumulation in TAMs. This metabolic alteration promoted membrane localization of the costimulatory molecule OX40L in a lipid modification–dependent manner, thereby activating CD8+ T cells. These findings unveil a previously unrecognized role for NOD1 in fortifying antitumor T cell immunity in HCC, potentially advancing cancer immunotherapy.
研究领域:
肿瘤学
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免疫学
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癌症生物学
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STAR Protocols
·
2021
·
IF 0
Zhengxin Peng,Man Yu,Jiaming Lin,Tianqi Dong,Xiao Zhang,Mingjun Shi,Min Qin,Shasha Li,Wencong Guo,Huixia Zhang,Shuguo Sun
Summary Anti-PD-1/PD-L1 therapy shows long-term effects in many cancer types, but resistance and relapse remain the main limitations of this therapy. Here, we describe a protocol to evaluate the tumor response to immunotherapy in a mouse lung cancer model. The protocol includes the establishment of the lung cancer mouse model, anti-PD-1 treatment, tumor-infiltrating lymphocyte isolation, immunofluorescence, and flow cytometry analysis. This protocol can also be applied to other cancer types and immunotherapies. For complete details on the use and execution of this protocol, please refer to Yu et al. (2021)
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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Cancer Communications
·
2023
·Vol. 43
·期 5
·562-581
·
IF 16.2
Zhaowei Wen,Huiying Sun,Zhihua Zhang,Yannan Zheng,Siting Zheng,Jianping Bin,Yulin Liao,Min Shi,Rui Zhou,Wangjun Liao
Background Several clinical studies have uncovered a negative correlation between baseline tumor burden and the efficacy of immune checkpoint inhibitor (ICI) treatment. This study aimed to uncover the specific mechanisms underlying the difference in sensitivity to ICI treatment between tumors with high (HTB) and low (LTB) tumor burden. Methods For in vivo studies, several mouse models of subcutaneous tumors were established, and transcriptome sequencing, immunohistochemistry, and flow cytometry assays were used to detect the immune status in these subcutaneous tumors. For in vitro experiments, co-culture models, cytokine antibody arrays, western blotting, flow cytometry, and enzyme-linked immunosorbent assays were used to explore the underlying molecular mechanisms Results We found that MC38 or B16 subcutaneous tumors from the HTB group did not show any response to anti-programmed cell death protein-1 (PD-1) therapy. Through flow cytometry assays, we found that the infiltration with CD8 + T cells was significantly decreased whereas M2-like macrophages were enriched in subcutaneous tumors of HTB groups compared with those of LTB group. These changes were not affected by the initial number of injected tumor cells or tumor age, nor could they be reversed by surgical tumor reduction. Intraperitoneal colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX3397 injection at different time points of tumor growth only had an effect when administered in the early tumor stage to maintain the “heat” of the tumor microenvironment during the process of tumor growth, thereby achieving a response to ICI treatment when the tumor grew to a large size. Mechanistically, we found that insulin-like growth factor binding protein 2 (IGFBP2) expression levels were significantly elevated in HTB tumor tissues. IGFBP2 promoted the programmed death-ligand 1 (PD-L1) expression in M2-like macrophages by activating signal transducer and activator of transcription 3 (STAT3), and PD-L1 + M2-like macrophages exerted an immunosuppressive effect by inhibiting the proliferation and activation of CD8 + T cells in a PD-L1-dependent fashion. Conclusions This study suggested that the low efficacy of ICI treatment in HTB tumors is mainly attributed to the intratumoral accumulation of PD-L1 + M2-like macrophages via the IGFBP2-STAT3-PD-L1 signaling pathway and their substantial inhibitory effects on T cell proliferation and activation.
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SENSORS AND ACTUATORS B-CHEMICAL
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2022
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IF 9.221
Minghui Wang,Yuxin Lin,Shuai Wu,Ying Deng,Yuanyuan Zhang,Jie Yang,Genxi Li
Programmed death-ligand 1 protein positive (PD-L1 + ) exosome is one of the most prospective biomarkers for the diagnosis of cancer. However, the current methods for the detection of PD-L1 + exosomes are usually laborious, time-consuming and require numerous samples. Herein, we report in this paper an electrochemical biosensor for PD-L1 + exosomes detection based on ultra-thin two-dimensional covalent organic framework nanosheets (2D COF NSs) coupled with clustered regularly interspaced short palindromic repeats (CRISPR) Cas 12a for signal amplification . Firstly, COF-367 NSs functionalized with gold nanoparticles (AuNPs) have been synthesized for the modification of the working electrode , thus the proposed sensor can show highly improved electrochemical performance. Secondly, by utilizing the trans-cleavage activity of Cas12a, this sensor can achieve very high sensitivity for the detection of PD-L1 + exosomes. With such design, the biosensor can have a linear range from 1.2 × 10 2 to 1.2 × 10 7 particles/μL with a detection limit of 38 particles/μL. Moreover, this sensor can be employed to analyze non-small cell lung cancer (NSCLC) patient serum samples, and successfully identify NSCLC patients, demonstrating the great potential in clinical applications.
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Materials Today Bio
·
2025
·
IF 10.2
Ling Wang,Jie Li,Danya Zhang,Songwei Tan,Guiying Jiang,Xueqian Wang,Fei Li,Ying Zhou,Pingbo Chen,Rui Wei,Ling Xi
Metastasis and recurrence are the main causes of failure in the treatment of ovarian cancer (OC). Immunotherapy has brought new opportunities for cancer treatment, but the presence of the immunosuppressive tumor microenvironment limits its application in OC. Here, we prepared a kind of intelligent nanomicelles that could inhibit OC metastasis and recurrence by combining photothermal tumor ablation and immune remodeling. In this study, Indocyanine green (ICG), a photosensitizer and Monophosphoryl lipid A (MPLA), a Toll-like receptor 4 agonist, were encapsulated into the core of PEG-PLGA nanocarrier, and the surface was further modified with tumor-targeting peptide TMTP1. The formed TP1-IM nanomicelles with enhanced tumor accumulation could enable robust photothermal ablation of the primary tumor, and induce immunogenic cell death, release tumor-associated antigens, and DAMPs to form an endogenous in situ tumor vaccine by a single intravenous injection, which could effectively inhibit the growth of OC. Moreover, PTT with TP1-IM nanomicelles in combination with programmed cell death ligand 1 (PD-L1) checkpoint blockade could induce strong anti-tumor immune responses, relieve the immunosuppressive tumor microenvironment, and thus effectively inhibit the metastasis of OC. In addition, the combination strategy could produce long-term immune memory effects in treated mice to prevent the recurrence of tumors. Our work provides a new and individualized strategy for the treatment of OC and is expected for clinical transformation in the future for most components are clinically approved.
研究领域:
癌症研究
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纳米医学
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免疫治疗
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生物医学工程
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CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Siyuan Meng,Fangnan Lv,Jieqing Chen,Linlin Tao,Hao Guo,Danhui Wang,Jie Sun,Jian Li,Ning Liu,Wei Xu,Meirong Huo
A biomimetic antigen outpost is engineered to sustainably co-deliver tumor antigens, siSOCS1, and Mn 2+ adjuvant. • Plasma gel recruits DCs to the injection site, while CRT on nanovaccines acts as an "eat-me" signal to enhance antigen uptake. • SOCS1 silencing and PD-L1 blockade synergistically empower DCs to more effectively prime and activate cytotoxic T lymphocytes (CTLs). • PD-L1 blockade further protects activated CTLs from tumor cell-mediated exhaustion, enabling sustained tumor killing and potent antitumor immunity in TNBC models. Tumor vaccines represent a promising immunotherapy approach but are challenged by rapid systemic clearance, low immunogenicity, and various immunosuppressive mechanisms. To overcome these issues, we created a biomimetic antigen outpost system to enhance vaccine delivery and immune activation. This system uses cationic 1,2-dihydroxybenzene-modified poly- l -lysine to co-load small interfering RNA targeting cytokine-suppressing factor 1 (siSOCS1) and immunoadjuvant (Mn 2+ ) as the core. This core is further coated with calreticulin (CRT)-enriched tumor cell membranes to form a nanovaccine (CRTM/PBM siSOCS1 ), which is ultimately encapsulated in a plasma gel (PG@CRTM/PBM siSOCS1 ). This design prolongs the vaccine's in vivo retention, recruits dendritic cells (DCs) by simulating subcutaneous hemorrhage signals, and enhances effective antigen uptake through CRT-mediated “eat me” signals. Upon DC internalization, the nanovaccine undergoes non-lysosomal trafficking, avoiding siSOCS1 degradation. The efficient SOCS1 silencing alleviates intracellular immunosuppressive feedback and, together with synergistic DC activation by antigens and Mn 2+ , further promotes DC maturation and antigen cross-presentation. In a triple-negative breast cancer model, the combination with anti-PD-L1 antibody simultaneously blocked PD-L1 on both mature DCs and tumor cells, significantly enhancing cytotoxic T lymphocyte function at both the immune priming and effector stages, and demonstrating potent antitumor efficacy. This multi-level intervention strategy provides a promising platform for enhancing cancer immunotherapy. Download: Download high-res image (112KB) Download: Download full-size image
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International Journal of Nanomedicine
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2026
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IF 8.7
Jing Zhang,Xiaoqiang Kong,Xiangping Wu,Dongyun Tao,Xiang Li,Huimin Cheng
Introduction Triple-negative breast cancer (TNBC) is an aggressive malignancy with poor prognosis, and Fusobacterium nucleatum (Fn) colonization further aggravates tumor progression, immunosuppression and therapeutic resistance. Conventional monotherapies are limited by insufficient tumor targeting, rapid drug clearance and failure to reverse immune suppression. Here, we fabricated cRGD-modified nanoparticles (Ag@GQDs/QUE-siP-c-L) for co-delivery of AgNPs, quercetin (QUE) and PD-L1 siRNA (siP).Methods The morphology, particle size, surface metal elements, drug content and QUE entrapment efficiency of Ag@GQDs/QUE-siP-c-L were obtained using particle size analysis, SEM, inductively coupled plasma-optical emission spectrometry (ICP-OES) and HPLC. We further detected cellular uptake, in vitro drug release, cytotoxicity, intracellular reactive oxygen species level, PD-L1 gene silencing efficiency and in vitro anti-Fn activity. Pharmacokinetics and tissue distribution of Ag and QUE were analyzed by ICP-OES and LC-MS/MS, and in vivo antitumor efficacy and biosafety were tested in Fn-colonized orthotopic 4T1 tumor mice.Results Ag@GQDs/QUE-siP-c-L exhibited uniform spherical morphology (195.87± 15.96 nm) with high encapsulation of QUE. cRGD modification enhanced Ag/QUE cellular uptake in 4T1 cells, with pH-responsive release accelerated under tumor acidic conditions. The nanoparticles exhibited selective tumor cytotoxicity, induced oxidative stress, downregulated PD-L1 mRNA, and exerted potent anti-Fn activity in vitro. Pharmacokinetics revealed increased AUC0-t and reduced clearance compared with free drugs, and cRGD modification promoted tumor accumulation and retention of drugs. In vivo preliminary experiments proved the Ag@GQDs/QUE-siP-c-L formulation suppressed tumor growth with a tumor inhibition rate of 45%, and effectively modulated the tumor immune microenvironment: it increased tumor-infiltrating CD3⁺CD4⁺ T cells, reduced PD-L1⁺CD11c⁺ dendritic cells, and decreased the proportions of immunosuppressive Tregs and MDSCs. Hematoxylin-eosin staining and serum liver-kidney biochemistry confirmed no obvious systemic toxicity.Conclusion Ag@GQDs/QUE-siP-c-L serves as a multimodal nanoplatform for Fn-associated TNBC with combined in vitro antibacterial, gene silencing and in vivo antitumor immunomodulatory effects, showing great potential for future translational research.
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Interdisciplinary Medicine
·
2026
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IF 14.5
Bo Pan,Shicui Hong,Xinyue Wang,Yanghang Li,Cai Wang,Yaxiao Liu,Ying Chen,Chen Fang,Yifeng Zheng,Shengqi Wang,Juping Zhang,Neng Wang,Zhiyu Wang
Triple-negative breast cancer (TNBC) remains a clinical challenge due to its high risk of recurrence and metastasis, coupled with limited responses to immunotherapy. Tumor-associated macrophages (TAMs) contribute to immunosuppression in the tumor microenvironment (TME) through C-X-C motif ligand 1 (CXCL1) secretion, but their targeting is hindered by poor drug delivery efficiency and physical barriers imposed by cancer-associated fibroblasts (CAFs). To address this, we developed a TAM-targeting black phosphorus nanosystem (αM2-BP-BHS, MBB) loaded with Baohuoside I (BHS), a known inhibitor of TAM polarization and CXCL1 secretion. In vitro and in vivo studies demonstrated that MBB efficiently targets TAMs and penetrates CAF barriers via photothermal activation under 808 nm near-infrared (NIR) irradiation, significantly enhancing BHS-mediated suppression of TAM/CXCL1 signaling. Furthermore, MBB-mediated photothermal therapy (PTT) boosted the memory T cell population, CD8 + T-cell infiltration and cytotoxic cytokine expression. When combined with anti-PD-L1 therapy, MBB synergistically suppressed TNBC progression and metastasis while establishing durable anti-cancer immunity to prevent recurrence. Notably, MBB exhibited excellent biocompatibility with minimal off-target effects, underscoring its potential as a precision delivery platform for BHS. Our findings highlight MBB as a promising adjuvant to potentiate immunotherapy in TNBC by concurrently overcoming stromal resistance and reprogramming immunosuppressive TME.
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Gland Surgery
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2022
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IF 2.16
Meili Zhang,Jialei Gu,Wendong Wang,Kejing Wang,Linfeng Zheng,Jianguo Feng,Jinbiao Shang
Background Identifying the high recurrence group of patients with early-stage papillary thyroid cancer (PTC) is the greatest challenge in the management of this disease. It has been noted that B-type Rafkinase (BRAF) V600E mutation and programmed death ligand 1 (PD-L1) are associated in PTC and highly expressed in PTC, correlating in PTC as potential prognostic biomarkers. However, whether they can be used to predict the aggressiveness and recurrence of early PTC remains unclear. Methods Clinicopathological data of 137 patients with early PTC [tumor-node-metastasis (TNM) stage I–II] who underwent surgery in Zhejiang Cancer Hospital between 2008 and 2010 were retrospectively analyzed. BRAF V600E mutation and PD-L1 was detected by immunohistochemistry. The median follow-up time was 136 months (interquartile range 5.8). The presence of tumor confirmed by imaging or pathology or lymph node metastasis was considered as tumor recurrence. The association of both alone and in combination with clinicopathological features and recurrence was statistically analyzed respectively. The risk of recurrence was assessed using Cox regression models. Results Most of the 137 early PTC were female (78.1%). The mean age was 43.2±12.1 years. The median tumor size was 1.4 cm; 14 patients developed recurrence during follow-up period; 56 patients (40.9%) were detected positive for BRAF V600E mutation; 76 patients (55.5%) were detected positive for PD-L1. Patients with both BRAF V600E mutation and PD-L1 expression had larger tumors (P=0.038), were more likely to have extrathyroidal invasion (P=0.045), and had a lower rate of cervical lymph node metastasis (P=0.046). The recurrence rate was 17.5% (7/40) in patients with BRAF V600E mutation and PD-L1 double expression compared to 8.9% (4/45) in patients with BRAF V600E mutation and PD-L1 double negative [hazard ratio (HR) =1.267; 95% CI: 0.841–1.909; P=0.257]. Survival curves showed flatter recurrence-free survival (RFS) curves in positive BRAF V600E mutation only and PD-L1 expression only, whereas decreased sharply in positive expression of both BRAF V600E mutation and PD-L1; however, the differences were not significant (P>0.05). Conclusions The combination of BRAF V600E mutation and PD-L1 to identify group at higher risk of recurrence in early PTC has insufficient clinical evidence and should be used with caution in the clinical management of PTC.
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