ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Yang Tang,Qun Jiang,Rongli Chen,Siqi Wu,Yichang Luo,Xi Huang,Guofang Yu,Cui Shao
Recent advances in immune checkpoint inhibitors (ICIs), particularly those targeting PD-1/PD-L1, have transformed cancer treatment. However, their efficacy is often hampered by the immunosuppressive tumor microenvironment (TME). Here, we developed a cantharidin-loaded nanomedicine (CA@TPGS-AmP), composed of D-α-tocopheryl polyethylene glycol succinate (TPGS) and naturally derived amphiphilic peptides (AmP), designed to enhance PD-1 blockade via induction of immunogenic cell death (ICD). In vitro, CA@TPGS-AmP markedly improved the solubility of cantharidin and exhibited superior penetration in 3D tumor spheroids. It effectively triggered key ICD events, including calreticulin (CRT) surface exposure, ATP release, and HMGB1 translocation, thereby promoting dendritic cell (DC) maturation. In vivo, CA@TPGS-AmP significantly augmented the antitumor efficacy of PD-1 therapy in 4T1 orthotopic breast cancer and LLC lung cancer models. Mechanistically, the combination therapy remodeled the TME into an immunostimulatory state by increasing CD8+ T cell infiltration and activation, leading to enhanced tumor suppression compared to monotherapies. These findings support CA@TPGS-AmP as a promising adjunct to PD-1 blockade and highlight the potential of natural product-based nanomedicine in advancing cancer immunotherapy.
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高影响因子
Translational Cancer Research
·
2025
·Vol. 14
·期 10
·6454
·
IF 1.7
Jiaxuan Zhao,Han Wu,Zhe Sun,Yeting Cui,Nan Liu,Yixuan Wang,Youyong Wang,Jiangzhou Shi,Tongcun Zhang
Background Chimeric antigen receptor T cell (CAR-T) therapy targeting cluster of differentiation 19 (CD19) has shown promise in treating B-cell acute lymphoblastic leukemia (B-ALL), but the long-term efficacy of CD19-targeted CAR-T therapy remains limited. Programmed cell death protein 1 (PD-1), an inhibitory receptor on activated T cells, engages programmed death ligand 1 (PD-L1) in the tumor microenvironment, suppressing CAR-T cell function by impairing key signaling pathways. To address this limitation, we investigated the effect of short hairpin RNA (shRNA)-mediated PD-1 knockdown on alleviating CAR-T cell exhaustion, preserving memory phenotype, and enhancing the long-term efficacy of CD19-targeted CAR-T cells. Methods To overcome this limitation, we employed shRNA to achieve PD-1 knockdown in CD19-targeting CAR-T cells. Following screening multiple shRNA candidates, we assessed the cytotoxicity, cytokine secretion, and proliferation of PD-1 knockdown CAR-T cells. Their memory phenotype, exhaustion marker, and cytolytic function were further evaluated after repeated antigen stimulation. Therapeutic efficacy and safety were validated in NOD.Cg-PrkdC scid Il2rg tm1 /Vst (NPG) mice. Results PD-1 knockdown significantly enhanced CAR-T cell cytotoxicity and persistence against PD-L1+ RAJI (human Burkitt’s lymphoma cell line) cells. After three rounds of antigen stimulation, PD-1 knockdown CAR-T cells sustained cytotoxic activity, retained a memory-like phenotype, and displayed attenuated exhaustion markers. In vivo , they prolonged survival without inducing cytokine release syndrome (CRS), indicating improved efficacy and safety. Conclusions PD-1 knockdown mitigates tumor-induced T-cell exhaustion and represents a promising strategy to enhance the durability and potency of CAR-T cell therapy in cancer treatment.
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高影响因子
ARCHIV DER PHARMAZIE
·
2025
·Vol. 358
·期 12
·e70155
·
IF 3.6
Xinli Wang,Xia Wang,Xuejing Su,Zexin Wang,Yongxiao Sun,Lijun Xie,Xiaoyan Lin
The development of theranostic probes with tumor-specific targeting and high therapeutic efficacy remains a pivotal challenge in precision oncology. Herein, we have successfully developed a new cyclooxygenase-2 (COX-2)-targeted probe compound 2 derived from Rofecoxib. Compound 2 facilitated tumor visualization by a sixfold fluorescence enhancement upon COX-2 binding, while it exhibited minimal background fluorescence under physiological conditions. Moreover, compound 2 monotherapy achieved 53% tumor regression ( p < 0.01). When combined with a programmed cell death protein 1 (PD-1) inhibitor (RMP1-14), concurrent blockade of the COX-2/prostaglandin E2 (PGE2) and PD-1/programmed death-ligand 1 (PD-L1) axes achieved 95% tumor regression ( p < 0.001). Compound 2 involves activating fluorescence by targeting tumor markers COX-2 as well as enhancing therapeutic efficacy. We believe this approach could provide insights for advancing cancer diagnosis and treatment technologies.
研究领域:
肿瘤学
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分子影像学
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免疫治疗
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药物化学
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精准医学
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PubMed
高影响因子
Cell Reports Medicine
·
2026
·
IF 14
Pengcheng Zhang,Yahui Gao,Yaxin Wang,Xin Li,Yi Jiang,Yigang Xu,Keliang Xie,Yixuan Ma,Sheng Wang,Hui Zheng,Wen Li,Xu Jin
A critical challenge in sepsis treatment lies in its complex immune microenvironment, characterized by concurrent hyperinflammation and immunosuppression. This imbalance is jointly driven by dysregulated neutrophil programmed death and abnormal activation of the PD-1/PD-L1 immune checkpoint. Therefore, precisely modulating neutrophil fate and blocking this immune checkpoint are highly promising therapeutic strategies. We engineered an artificial exosome nano-decoy (AT@NV-PD1) that homes to senescent-like neutrophils. It comprises a pH-responsive bovine serum albumin core carrying AT7519, a cyclin-dependent kinase inhibitor, cloaked with macrophage membrane presenting PD-1. After intravenous delivery, PD-1 selectively binds PD-L1 on target neutrophils. In the mildly acidic microenvironment, AT7519 release triggers timely neutrophil apoptosis, curbing excessive inflammation. Concurrently, the nano-decoy neutralizes bacterial toxins and inflammatory cytokines. By engaging PD-L1, AT@NV-PD1 also alleviates T cell exhaustion, reduces immunosuppression, and promotes immune homeostasis. In conclusion, AT@NV-PD1 represents a sepsis therapy by precisely regulating neutrophil fate and rebuilding immune balance.
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CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Fei Kong,Zhiqiang Zeng,Xiaorong Zhu,Qingqing Wu,Lu Zhou,Changwei Dou,Zhongbo Xie,Lidong Cao
The combination of photodynamic therapy and immunotherapy has emerged as a safe and effective cancer treatment strategy. However, traditional photodynamic therapy and precision anti-tumor immunotherapy still face challenges, such as weak light source penetration, poor targeting specificity, low response rates and immune-related adverse effects. Herein, a smart polymer nano-immunomodulator (SPNI) that can respond to the tumor microenvironment for precise photodynamic immunotherapy of cancer is reported. This SPNI is self-assembled from pH and glutathione (GSH) bi-responsive amphiphilic polymers, simultaneously loaded with photosensitive materials and oxygen-carrying molecules, subsequently is wrapped by hepatocellular carcinoma (HCC) cell membrane using a simple coextrusion method to generate biomimetic nanoparticles. Upon reaching the tumor site, the SPNI degrades in the tumor microenvironment, effectively releasing photosensitive substances with chemophotodynamic effects to directly eliminate tumors without an external light source. Additionally, the immunosuppressant blocks PD-1/PD-L1 signaling pathways to enhance the body’s endogenous anti-tumor immune response, inhibiting tumor growth and metastasis. Furthermore, the incorporated immunosuppressant effectively blocks PD-1/PD-L1 signaling pathways, thereby potentiating endogenous anti-tumor immune responses to suppress both primary tumor growth and metastatic progression. This innovative combination of tumor microenvironment-responsive photodynamic therapy and checkpoint blockade immunotherapy demonstrates remarkable efficacy in anti-HCC treatment and shows substantial potential for clinical translation. The SPNI platform represents a significant advancement in precision cancer therapy by simultaneously addressing multiple limitations of current treatment modalities.
研究领域:
医学
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生物材料学
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肿瘤学
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ACS Applied Materials & Interfaces
·
2020
·
IF 8.758
Wei Zhang,Cun-cheng Zhang,Xing-Yue Wang,Lin Li,Qiao-Qi Chen,Wei-Wei Liu,Yang Cao,Hai-Tao Ran
Photothermal therapy (PTT) as a noninvasive and effective thermal therapeutic approach has attracted tremendously increasing interest because it can effectively eliminate the primary tumor and generate tumor-associated antigens, which could elicit antitumor immune responses. Herein, we report on the rational design and fabrication of copper sulfide (CuS)-based nanoplatform for cancer photothermal immunotherapy. The as-prepared core–shell CuS@mSiO2-PFP-PEG (CPPs) nanocomposites possess high biocompatibility, photoacoustic (PA)/ultrasound (US) imaging, and strong PTT effect upon 808 nm laser irradiation, indicating that the nanocomposites have a promising application in diagnosis and treatment of breast cancer with molecular classification. Importantly, we also elucidated that the CPP-triggered PTT in combination with anti-PD-1 checkpoint blockade therapy can not only obliterate primary tumor but also inhibit metastatic tumor in tumor-bearing mice. We believe that the CPPs have a good probability to serve as a useful nanoplatform for PTT, and this approach may provide a promising strategy for tumor-therapeutic modality with immunotherapy.
研究领域:
肿瘤学
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生物医学工程
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纳米医学
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·
IF 12.6
Shijin Xu,Naidi Yang,Fangning Du,Ziying Zhang,Yin Zhang,Yixuan Zhang,Jiawei Liang,Yihan Zhao,Jiajun Zhang,Ziwei Zhang,Xiaoxuan Han,Zena Chen,Zhiqiang Zhou,Shu Zhang,Lin Li,Ying Lv
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, marked by extensive stromal fibrosis and a profoundly immunosuppressive, immune-excluded tumor microenvironment (TME) that hampers the efficacy of immune checkpoint blockade. Although photodynamic therapy (PDT) can induce immunogenic cell death (ICD) and stimulate anti-tumor immunity, its effectiveness against PDAC is limited by insufficient immune activation and persistent stromal-mediated immunosuppression. To address these challenges, we develop a liposomal nanodrug that co-encapsulates a mitochondrial-targeted photosensitizer (MP) and a TGF-β receptor inhibitor (LY2109761) to synergize PDT with PD-1 checkpoint blockade. MP selectively accumulates in mitochondria and, upon light activation, amplifies mitochondrial reactive oxygen species production, inducing mitochondrial damage. This damage triggers the release of mitochondrial DNA and damage-associated molecular patterns, activating the STING pathway and eliciting potent ICD and anti-tumor immune responses. Simultaneously, liposome-mediated delivery of LY2109761 mitigates stromal desmoplasia and reverses TGF-β-driven immune suppression, enhancing effector T cell infiltration and activity. In murine PDAC models, this dual-action strategy transforms the immune-cold TME into an immune-inflamed phenotype, sensitizing tumors to PD-1 therapy and leading to pronounced tumor regression and prolonged survival. Our findings present a promising nanodrug-based approach to remodel the fibrotic and immunosuppressive TME of PDAC and enhance immunotherapeutic outcomes.
研究领域:
肿瘤学
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免疫治疗
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纳米医学
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光动力治疗
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肿瘤微环境
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分子生物学
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2026
·
IF 15
Zhao Mengfei,Zhang Jichuan,Guan Meng,Li Xuanhan,Sun Huating,Mao Kuirong,Tan Huizhu,Zhang Yijia,Meng Xandi,Cong Xiuxiu,Xin Yanbao,Wang Haorui,Yu MeiLing,Chen Si,Zhou Hongxv,Wang Xinhe,Yang Yong-Guang,Sun Tianmeng,Zhang Yuning
Immune checkpoint blockade (ICB) remains limited by the immunosuppressive tumor microenvironment (TME) and by the difficulty of coordinating therapeutic agents that act in distinct tumor compartments. In particular, checkpoint antibodies must function in the tumor stroma, whereas TME-remodeling small molecules often require intracellular access, creating an extracellular–intracellular delivery mismatch that conventional carriers rarely resolve. Here, we develop an acid-gated, esterase-amplified AND-gated dendritic nanogel (DNG) for the spatiotemporally sequential codelivery of anti-PD-1 antibody (aPD-1) and the PPARδ antagonist GSK3787. The DNG comprises a PEG corona for reversible aPD-1 adsorption and a hydrophobic dendritic core for GSK3787 encapsulation. Under the combined cues of tumor acidity and esterase activity, the nanogel undergoes progressive dissociation, triggering preferential extracellular release of aPD-1 in the tumor stroma, followed by tumor-cell internalization of the GSK3787-loaded core for intracellular drug action. This AND-gated design enables spatially resolved pharmacology rather than simple codelivery. In a melanoma model, DNG@(GSK3787 + aPD-1) markedly enhances antitumor efficacy, thereby promotes CD8⁺ T cell infiltration, and elicits systemic antitumor immune responses. Mechanistically, we identify a tumor cell-centric mode of immune remodeling and further show that the dendritic core actively governs not only small-molecule encapsulation, but also antibody retention and triggered release. Together, this work establishes a materials strategy for overcoming extracellular–intracellular delivery mismatch in combination immunotherapy. Graphical AND-gated dual-responsive nanogel enables spatiotemporally sequential extracellular delivery of aPD-1 and intracellular delivery of GSK3787, thereby overcoming the extracellular–intracellular delivery mismatch and synergistically remodeling the tumor immune microenvironment for enhanced cancer immunotherapy.
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MOLECULAR THERAPY
·
2026
·
IF 11.4
Yang Yang,Jiannan Wang,Hong Yu,Zhen Quan,Zhujiao Zhang,Jingran Guo,Haoxuan Wu,Shanshan Liu,Xiaoqian Li,Xinxin Hu,Hongyan Zou,Mengyuan Zhu,Tianyi Wang,Zijian Zhou,Jiaying Liu,Jing Wang,Kai Wang,Lili Yang,Zhaoguo Han,Xilin Sun
The costimulatory receptor CD28 is indispensable for regulating T-cell effector function, and the absence of co-stimulation is associated with poor immunotherapy response. However, longitudinal molecular imaging studies targeting CD28 as a costimulatory biomarker using positron emission tomography (PET) have not been reported. Here, we developed the co-stimulation-associated radiotracer [ 89 Zr]Zr-DFO-anti-CD28 to enable early prediction of therapeutic response by identifying recovery of T-cell responsiveness following programmed cell death protein 1 (PD-1) blockade in lung cancer. [ 89 Zr]Zr-DFO-anti-CD28 demonstrated high specificity for CD28 + tumor-infiltrating lymphocytes (TILs) in vitro and in vivo. By monitoring CD28 expression and its loss within the tumor microenvironment, [ 89 Zr]Zr-DFO-anti-CD28 PET identified responses to anti-PD-1 therapy earlier than changes in tumor volume observed at day 5, and increased radiotracer uptake correlated with more favorable treatment responses. Repeated PET imaging was performed to monitor dynamic changes in CD28 + TILs induced by different immunotherapies at day 14, and [ 89 Zr]Zr-DFO-anti-CD28 PET captured the CD28-dependent restoration of T-cell effector function, further supporting its potential for early prediction. Taken together, costimulatory biomarker-specific CD28 PET molecular imaging may enable noninvasive early prediction of responses to multiple immunotherapies and facilitate the application of precision medicine in lung cancer.
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高影响因子
iScience
·
2024
·
IF 4.6
Junyang Li,Bingjie Mei,Lu Feng,Xiaoxin Wang,Dengfeng Wang,Jianming Huang,Guonan Zhang
Reprogramming tryptophan metabolism (TRP) may be able to overcome immunosuppression and restore the immune checkpoint blockade (ICB) response in epithelial ovarian cancer (EOC) patients resistant to ICB therapy. Because TRP metabolism is involved in the kynurenine/indole and serotonin pathways of tryptophan metabolism. Herein, employing amitriptyline (AMI), an antagonist of TLR4 and serotonin transporter (SERT), we revealed that AMI remodels the immunological landscape of EOC. In particular, AMI lowered the expression of IDO1, IL-4I1 and PD-L1, the quantity of KYN and indoles, and the level of immunosuppressive immune cells MDSC, Tregs and CD8+CD39+/PD-1+ T cell. AMI boosted the killing potential of anti-PD-1-directed CD8+T cells and worked in concert with PD-1 inhibitor to suppress tumor growth and to prolong the survival of EOC-bearing mice. This work highlights AMI as an effective regulator of ICB response by manipulating EOC cell TRP metabolism, indicating it could be a potential strategy for improving EOC ICB therapy.
研究领域:
肿瘤学
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免疫学
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药理学
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PubMed
高影响因子
Cancer Communications
·
2026
·
IF 28.4
Chenchen Hu,Feiming Hu,Changjian Shao,Yuanli He,Liping Su,Daimei Shi,Lingying Yu,Yuanjie Sun,Jing Wang,Xiyang Zhang,Hongtao Duan,Junqi Zhang,Yubo Sun,Dongbo Jiang,Xiaolong Yan,Shuya Yang,Kun Yang
Background: Lung cancer remains a major global health burden. RNA-binding proteins (RBPs) play crucial roles in post-transcriptional gene regulation, and their dysregulation is frequently implicated in tumorigenesis. The present study aimed to elucidate the molecular network governed by the highly expressed RBP TIMELESS in lung adenocarcinoma (LUAD) and determine its mechanistic role in LUAD progression. Methods: The Cancer Genome Atlas-LUAD, Gene Expression Omnibus, and single-cell RNA sequencing datasets were analyzed to identify aberrantly expressed RBP genes. The RBP gene TIMELESS exhibited the most significant effect on LUAD cell death and was selected for further study. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation sequencing and RNA sequencing were employed to identify ferroptosis-related targets directly bound by TIMELESS. Molecular mechanisms underlying the TIMELESS-mediated regulation of ferroptosis in LUAD were investigated via immunoprecipitation–mass spectrometry, glutathione S -transferase pull-down, immunofluorescence–fluorescence in situ hybridization, RNA immunoprecipitation, poly(A)-tail, and RNA stability assays. In an orthotopic lung cancer mouse model treated with erastin (a ferroptosis inducer) and programmed cell death protein 1 (PD-1) blockade, the role of TIMELESS in therapeutic response was assessed via flow cytometry and multiplex immunofluorescence (mIF). Infiltrating immune cells in LUAD were analyzed by tissue microarrays (TMAs) via mIF. Results: TIMELESS significantly affected LUAD cell proliferation and death, and TIMELESS knockdown significantly enriched RNA-binding and ferroptosis pathways. Transferrin (TF) was identified as a direct TIMELESS target governing ferroptosis. TIMELESS was revealed to bind Ccr4-Not transcription complex subunit 3 (CNOT3) to promote TF mRNA degradation. TIMELESS depletion combined with erastin and PD-1 blockade enhances efficacy, prolongs survival, increases T cell and M1 macrophage infiltration, and reduces M2 macrophage infiltration. Further, high TIMELESS expression was inversely correlated with ferroptosis marker 4-hydroxynonenal but positively correlated with programmed cell death ligand 1 (PD-L1), reduced T cell and M1 macrophage infiltration, and increased M2 macrophage infiltration. Conclusions: TIMELESS recruits CNOT3 to accelerate TF mRNA degradation, thereby suppressing ferroptosis and promoting LUAD growth. These findings suggest that the TIMELESS/TF regulatory axis may be a promising therapeutic target for LUAD.
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高影响因子
BMC MICROBIOLOGY
·
2024
·Vol. 24
·期 1
·1-15
·
IF 4
Wang Benlin,Qiu Yifeng,Xie Ming,Huang Pengcheng,Yu Yao,Sun Qi,Shangguan Wentai,Li Weijia,Zhu Zhangrui,Xue Jingwen,Feng Zhengyuan,Zhu Yuexuan,Yang Qishen,Wu Peng
Objective Bladder cancer(BCa) was a disease that seriously affects patients’ quality of life and prognosis. To address this issue, many researches suggested that the gut microbiota modulated tumor response to treatment; however, this had not been well-characterized in bladder cancer. In this study, our objective was to determine whether the diversity and composition of the gut microbiota or the density of specific bacterial genera influence the prognosis of patients with bladder cancer. Methods We collected fecal samples from a total of 50 bladder cancer patients and 22 matched non-cancer individuals for 16S rDNA sequencing to investigate the distribution of Parabacteroides in these two groups. Further we conducted follow-up with cancer patients to access the impact of different genera of microorganisms on patients survival. We conducted a Fecal Microbiota Transplantation (FMT) and mono-colonization experiment with Parabacteroides distasonis to explore its potential enhancement of the efficacy of anti-PD-1 immunotherapy in MB49 tumor-bearing mice. Immunohistochemistry, transcriptomics and molecular experiment analyses were employed to uncover the underlying mechanisms. Results The 16S rDNA showed that abundance of the genus Parabacteroides was elevated in the non-cancer control group compared to bladder cancer group. The results of tumor growth curves showed that a combination therapy of P. distasonis and ICIs treatment significantly delayed tumor growth and increased the intratumoral densities of both CD4 + T and CD8 + T cells. The results of transcriptome analysis demonstrated that the pathways associated with antitumoral immune response were remarkably upregulated in the P. distasonis gavage group. Conclusion P. distasonis delivery combined with α-PD-1 mAb could be a new strategy to enhance the effect of anti-PD-1 immunotherapy. This effect might be achieved by activating immune and antitumor related pathways.
研究领域:
肿瘤学
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微生物学
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免疫学
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分子生物学
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高影响因子
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