BIOMATERIALS
·
2025
·
IF 12.9
Zhanxue Xu,Xinrui Yang,Xingyu Lu,Dandan Su,Yidan Wang,Huixing Wu,Zhenhua Zhang,Changrui Long,Liqian Su,Yanyu Wang,Hongbo Chen,Shijian Xiang,Benjie Zhou
Combination therapies for melanoma face challenges due to asynchronous drug delivery and associated toxicity, underscoring the need for advanced delivery systems. While immune checkpoint inhibitors (ICIs) enhance T cell activity, optimal cytotoxic responses require efficient antigen presentation by mature dendritic cells (DCs), which are often functionally impaired in the tumor microenvironment. Thus, effective treatment requires coordinated T cell activation, DC-mediated priming, and direct tumor suppression. Herein, wild Glycyrrhiza uralensis Fisch roots-derived nanovesicles (GC NV) are demonstrated to be effective inhibitors of melanoma proliferation. The vesicles exert this activity through the intracellular delivery of encapsulated miRNA (miR2916) and bioactive molecules (isoliquiritigenin), with this capacity for intracellular delivery extending to the STING agonist DMXAA. We also demonstrate how chemical modification can be used to install PD-L1 antibodies on the membrane surface of these GC NV, imbuing these vesicles with selectivity for tumor cells. Combining DMXAA encapsulation with surface-displayed PD-L1 antibodies creates vesicles (GP@DMX NV) that both promote DCs maturation and elicit CD8 + T cell response. Our multifunctional GP@DMX NV reverse the immunosuppressive microenvironment of melanoma and significantly enhance the immunotherapeutic potential of immune checkpoints.
研究领域:
肿瘤学
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药剂学
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免疫学
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产品关联
DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2025
·Vol. 21
·期 8
·3555
·
IF 10
Pengyi Liu,Minmin Shi,Yang Liu,Yihao Liu,Jiayu Lin,Shuyu Zhai,Yizhi Cao,Dongjie Chen,Yongsheng Jiang,Chenghong Peng,Lei Zhang,Chunyong Ding,Lingxi Jiang,Baiyong Shen
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited treatment options and poor response to immunotherapy. The immunosuppressive tumor microenvironment, characterized by a dense extracellular matrix, and immunosuppressive cells, plays a crucial role in this resistance. The cGAS-STING pathway, traditionally recognized for antiviral defense, has emerged as a potential target for cancer immunotherapy due to its ability to activate both innate and adaptive immune responses. Methods: A novel small-molecule STING agonist, D166, was synthesized by incorporating deuterium into the structure, leading to improved stability and activation of the STING pathway. The effects of D166 were evaluated using human pancreatic tumor organoids, mouse pancreatic tumor models, and various in vitro and in vivo assays, including flow cytometry, RNA sequencing, ELISA and western blotting. And an organoid-immune cells co-culture system was established for further investigate the effects on immune cells. Results: D166 demonstrated significant anti-tumor activity, effectively activating the cGAS-STING pathway in a time- and dose-dependent manner. D166 inhibited the progression of pancreatic tumor organoids and mouse pancreatic tumors, reshaping the tumor immune microenvironment. The drug enhanced T cell activation, promoted macrophage polarization toward the M1 phenotype, and increased the infiltration of immune cells. Additionally, D166 acted as a sensitizer for anti-PD-1 therapy, significantly improving therapeutic efficacy in combination treatments. Conclusion: D166 is a novel and stable STING agonist that inhibits pancreatic tumor progression by activating the cGAS-STING pathway and remodeling the tumor immune microenvironment. Its combination with anti-PD-1 antibodies offers a promising strategy for overcoming the immunosuppressive barriers in pancreatic cancer, providing new therapeutic insights and directions.
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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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Huajing Yang,Rui Li,Shiyang Jin,Yuhang Tian,Chunyue Wang,Yucao Sun,Zhifei Dai,Wen Cheng
Hepatocellular carcinoma (HCC) is the most common primary malignant disease of the liver. Although immunotherapy offers new opportunities for treating advanced HCC, its therapeutic effect is still limited by the immunosuppressive tumor microenvironment (TME). Herein, a nanosensitizer RGD@Ce6@MSA-2@Liposome (RCM-Lip) is synthesized to specifically initiate the HCC tumor immune microenvironment through sonodynamic therapy (SDT)-triggered immunogenic cell death (ICD) and MSA-2-activated cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. RCM-Lip consists of a sonosensitizer (Chlorin e6, Ce6) with a STING agonist (MSA-2) and a tumor targeting peptide RGD inserted on the outer liposome surface. Under ultrasound irradiation, RCM-Lip generates reactive oxygen species that induce cytotoxicity and apoptosis of tumor cells. Meanwhile, tumor antigens released by apoptosis are taken up by dendritic cells (DCs), while STING is activated in the DCs by MSA-2. Moreover, DC maturation is stimulated, further enhancing the systematic anti-tumor immune responses. Sono-immunotherapy mediated by RCM-Lip promotes DCs maturation and tumor infiltration of CD8 + T cells, increasing inflammatory cytokine secretion. Consequently, the immunologically “cold” TME of HCC is successfully turned into a “hot” one, leading to a significant tumor suppression effect with good bio-safety. These results suggest a promising method for precise tumor targeting and synergistic cancer sono-immunotherapy. Statement of Significance Our study addressed the therapeutic dilemma of hepatocellular carcinoma (HCC) as an immunological “cold” tumor by the synergistic application of sonodynamic therapy (SDT) and STING agonist. The cGAS-STING signaling pathway plays a pivotal role in innate immunity against cancer, but the clinical application of STING agonists were hampered by inflammatory responses due to off-target activation. Our innovative solution introduces RGD-targeted peptide to encapsulate sonosensitizer and STING agonist, strengthening therapeutic effects and reducing systemic toxicity. The targeted sono-immunotherapy promoted DCs maturation and tumor infiltration of CD8 + T cells, producing intense tumor-killing effect on mice model with good bio-safety. As a result, the immunological “cold” tumor microenvironment of HCC is successfully turned into a “hot” one.
研究领域:
肿瘤学
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免疫学
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医学工程
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Jian Wu,Zhiqiang Chen,Haojie Shang,Yonghua Tong,Wen Deng,Yu He,Xiaozhuo Ba,Zichen Zhong,Yongke Bai,Tao Ye,Xiaoqi Yang,Kehua Jiang,Yijing Liu,Kun Tang
Limited lymphocyte infiltration and insufficient tumor immunogenicity remain major challenges for effective immunotherapy in bladder cancer, particularly in immunologically “cold” tumors with a highly suppressive immune microenvironment. Effective activation of the innate immune system is critical for initiating a robust adaptive anti-tumor immune response, primarily mediated by dendritic cells (DCs). Here, we designed genetically engineered hybrid membrane-coated nanoparticles (HM-MPS NPs) with excellent photothermal stability, tumor-targeting capability, and biocompatibility. HM-MPS NPs demonstrated significant tumor-suppressive effects in multiple preclinical models, including murine subcutaneous, orthotopic, and distant bladder tumor models. By combining photothermal therapy (PTT), a STING agonist (SR717), and antigen presentation, HM-MPS NPs achieve triple activation of DCs, leading to enhanced T-cell activation and a remodeled immune microenvironment. Furthermore, HM-MPS NPs synergize effectively with anti-PD-1 therapy, amplifying immunogenic cell death (ICD) and overcoming immune suppression within the tumor microenvironment. This strategy significantly boosts tumor immunogenicity and enhances anti-tumor immune responses, offering a promising approach for bladder cancer treatment.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
高影响因子
Bioactive Materials
·
2025
·
IF 20.3
Guoqing Zhong,Yali Miao,Jielong Zhou,Yijie He,Wenjie Yang,Chongquan Huang,Yunhui Zhang,Jin Xiao,Bingqing Bai,Jiaqi Zhou,Renshan Li,Tiantian Wei,Yu Zhang,Shi Cheng
Approximately half of lung cancer patients experience bone metastasis, leading to bone loss, fracture, and other skeletal-related events. Although immunotherapies have significantly advanced the therapeutic landscape for lung cancer, bone metastases have an immunologically "cold" microenvironment, representing a challenging obstacle when treating lung cancer. The combination of immunotherapy and photothermal therapy (PTT) for treating tumor-induced bone defects holds promise for enhancing the efficacy of local tumor ablation and inhibiting tumor recurrence and metastasis through activating systemic immune responses. Herein, we developed an injectable hydrogel-based photothermal immunotherapy system (BP@Gel-CD[SA] hydrogel) incorporating STING agonists (SA) and black phosphorus nanosheets (BPNSs) for high-efficiency tumor elimination, immune activation, and bone regeneration. The photothermal and photodynamic activities of BPNSs induce hyperthermia and ROS-mediated apoptosis of tumor cells. Meanwhile, SA loaded into the nano-boxes in BP@Gel-CD[SA] hydrogel by host-guest interaction significantly activates the cGas-STING pathway. It stimulates immunogenic cell death (ICD), synergistically promoting immune cell infiltration. Single-cell RNA sequence analysis confirms the modulation of the tumor microenvironment (TME) through the PTT-mediated ICD effect and the transactivation of the cGAS-STING pathway in immune cells of the TME. More importantly, the system can significantly inhibit the growth of distant tumors via systemic immune activation and elicit long-term immune memory in addition to tumor eradication. In the long term, this hydrogel system can promote the formation of new bone at sites of tumor-induced bone destruction, improving bone strength in the affected area. Collectively, this strategy provides an effective and safe option for treating lung cancer bone metastases.
研究领域:
肿瘤学
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生物材料学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2022
·Vol. 9
·期 32
·2203523
·
IF 17.521
Ming Shen,Chuanrong Chen,Qianqian Guo,Quan Wang,Jinghan Liao,Liting Wang,Jian Yu,Man Xue,Yourong Duan,Jiali Zhang
T-cell engagers (TCEs) represent a breakthrough in hematological malignancy treatment but are vulnerable to antigen escape and lack a vaccination effect. The “immunologically cold” solid tumor presents substantial challenges due to intratumor heterogeneity and an immunosuppressive tumor microenvironment (TME). Here, a methoxy poly(ethylene glycol) (mPEG)-masked CD44×PD-L1/CD3 trispecific T-cell nanoengager loaded with the STING agonist c-di-AMP (CDA) (PmTriTNE@CDA) for the treatment of triple-negative breast cancer (TNBC) is rationally designed. PmTriTNE@CDA shows tumor-specific accumulation and is preferentially unmasked in response to a weakly acidic TME to prevent on-target off-tumor toxicity. The unmasked CD44×PD-L1/CD3 trispecific T-cell nanoengager (TriTNE) targets dual tumor-associated antigens (TAAs) to redirect CD8+ T cells for heterogeneous TNBC lysis while achieving PD-L1 blockade. PmTriTNE synergized with CDA to transform the cold tumor into a hot tumor, eradicate the large established TNBC tumor, and induce protective immune memory in a 4T1 orthotopic tumor model without causing obvious toxicity. PmTriTNE@CDA shows potent efficacy in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. This study serves as a proof-of-concept demonstration of a nanobased TCEs strategy to expand therapeutic combinations that previously could not be achieved due to systemic toxicity with the aim of overcoming TNBC heterogeneity and immunotherapy resistance.
研究领域:
肿瘤学
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免疫学
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纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Zubair Hussain,Shanshan Gou,Xu Liu,Mengyu Li,Hanyue Zhang,Sumei Ren,Ruxia Han,Fangfang Liu,Xiaowen Zhou,Lu Qiu,Hongfei Wang,Zhenzhen Chen,Kangdong Liu
Immunotherapy has significantly advanced cancer treatment, but the tumor immune microenvironment (TIME) often remains immunosuppressive, limiting therapeutic efficacy. Tumor-associated macrophages (TAMs), particularly M2-like macrophages, play a crucial role in promoting tumor growth and immune evasion. Our study introduces a novel approach using dual-targeted ZrMOF/C@P nanoparticles, smartly engineered with cell membrane coating and enzyme responsiveness, to effectively modulate TAMs. These nanoparticles are synthesized and loaded with 2’, 3’-cGAMP, a STING agonist, and encapsulated in a peptide-expressed macrophage membrane (PMM) featuring Pep20, MMP2, and M2pep. In vitro , they activate the STING pathway in M2-like macrophages and reprogram them into M1-like macrophages. Smart ZrMOF/C@P is found to accumulate at the tumor even 72 hours post-injection. In CT26 and 4T1 tumor models show that smart ZrMOF/C@P not only suppresses tumor growth but also stimulates systemic immune responses. This is evidenced by a reduction in M2-like and an increase in M1-like macrophages, enhanced dendritic cell (DC) maturation, and increased tumor infiltration of CD4 + and CD8 + T cells, accompanied by elevated IFN-γ secretion. This innovative use of ZrMOF/C@P offers a promising strategy to transform the immunosuppressive TIME, presenting a versatile and effective treatment option for solid tumors, and novel avenue for non-CDN-STING agonists, facilitating systemic administration.
研究领域:
肿瘤学
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免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2024
·
IF 9.4
Yuqing Pan,Haijing Qu,Han Chen,Wei Cheng,Zhiran Duan,Jiaojiao Yang,Ning Wang,Jie Wu,Yanjun Wang,Chao Wang,Xiangdong Xue
The activation of STING pathway has emerged as a promising strategy in cancer immunotherapy. However, challenges associated with unfavorable physicochemical properties and potential off-target toxicities have limited the application of STING agonists. Here, we develop an amphiphilic and cationic charged porphyrin-polymer to electrostatically load the STING agonist (MSA-2) within a micellar structure, thereby enhancing carrier compatibility and drug-loading content of MSA-2. Additionally, tumor-targeting ligands were functionalized onto the micelle to enhance specificity for tumor cells, aiming to significantly improve tumor accumulation while minimizing undesirable toxicity. The resultant tumor-targeting porphyrin micelle (TPC@M) seamlessly integrates three therapeutic mechanisms: i) tumor ablation via phototherapy; ii) robust activation of the STING pathway by MSA-2; iii) synergistic photo-/immuno- stimulations. TPC@M efficiently ablates primary tumors through phototherapy and further activates adaptive immune responses synergistically with MSA-2-induced innate immunity to suppress metastasis and prevent recurrence. Overall, we transformed a delivery-compromised therapeutic into a precise, stable, and safe nanomedicine that unleashes synergistic immunotherapeutic effects. Statement of significance This study addresses the urgent need for an efficient delivery system to fully harness the potential of the STING agonist MSA-2 in cancer immunotherapy. The cGAS-STING pathway plays a critical role in modulating anti-tumor immunity; however, the clinical application of MSA-2 has been hindered by its poor physicochemical properties and off-target effects. Our innovative approach introduces a tumor-targeting porphyrin-based polymeric micelle (TPC@M) that efficiently encapsulates MSA-2, overcoming compatibility issues associated with traditional nanocarriers. The TPC@M not only exhibits enhanced tumor targeting and reduced toxicity but also integrates phototherapy with immunotherapy, providing a synergistic strategy for cancer treatment. Our in vivo findings using 4T1 breast cancer mouse models demonstrate significant inhibition of tumor growth and prevention of metastasis, accompanied by a robust and long-lasting immune response.
研究领域:
癌症免疫疗法
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纳米医学
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药理学
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肿瘤学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
·
2025
·
IF 10.9
Zhaochu Xu,Jiang Yu,Yingxi Zhang,Yue Wang,Wenxiao Li,Baoyue Zhang,Wenwen Cui,Yicheng Li,Yue Wang,Zimeng Yang,Yubo Liu,Xin Li,Yongjun Wang,Zhonggui He,Hongzhuo Liu
Cancer vaccine has emerged as a promising therapeutic paradigm for cancer therapy. However, the lack of tumor-associated antigens and abundant immunosuppressive factors seriously diminish the efficacy of immunotherapy, resulting in poor clinical benefits. In this report, we engineered a coordinated immunostimulatory nanoplatform, termed MP@PPS NPs, by physically combining reactive oxygen species (ROS)-responsive poly (propylene sulfide) nanoparticles loaded with the photosensitizer pyropheophorbide a (PPa) and stimulator of interferon genes (STING) agonist (MSA-2), to function as an in situ cancer vaccine to amplify immunotherapeutic outcomes. Excellent stability of MP@PPS NPs endowed prolonged drug circulation time and improved tumor accumulation, while their small size boosted deeper drug penetration within tumors. Crucially, upon laser irradiation, the MP@PPS NPs could generate abundant ROS, which induced tumor ablation, triggered immunogenic cell death to initiate an adaptive antitumor immune response and facilitated the local release of MSA-2, thereby promoting innate antitumor immunity through the cGAS-STING pathway. MP@PPS NPs markedly suppressed both primary and distant tumor progression, promoted dendritic cell maturation and increased cytotoxic T lymphocyte infiltration, elicited robust antitumor immunity. Meanwhile, MP@PPS NPs treatment impeded the lung metastatic in conjunction with anti-PD-L1 treatment. This work holds significant promise for the synergistic photodynamic immunotherapy, and offers a crucial inspiration for addressing the problems of insufficient antitumor immunity and ineffective cancer treatments.
研究领域:
肿瘤学
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免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
高影响因子
ACS Nano
·
2024
·
IF 15.8
Bin Wang,Maoping Tang,Qijing Chen,William Ho,Yilong Teng,Xiaojian Xiong,Zhitong Jia,Xiuling Li,Xiaoyang Xu,Xue-Qing Zhang
T cell exhaustion has emerged as a major hurdle that impedes the clinical translation of stimulator of interferon genes (STING) agonists. It is crucial to explore innovative strategies to rejuvenate exhausted T cells and potentiate the antitumor efficacy. Here, we propose an approach utilizing MSA-2 as a STING agonist, along with nanoparticle-mediated delivery of mRNA encoding interleukin-12 (IL-12) to restore the function of T cells. We developed a lipid nanoparticle (DMT7-IL12 LNP) that encapsulated IL12 mRNA. Our findings convincingly demonstrated that the combination of MSA-2 and DMT7-IL12 LNP can effectively reverse the exhausted T cell phenotype, as evidenced by the enhanced secretion of cytokines, such as tumor necrosis factor alpha, interferon gamma, and Granzyme B, coupled with reduced levels of inhibitory molecules such as T cell immunoglobulin and mucin domain-3 and programmed cell death protein-1 on CD8+ T cells. Furthermore, this approach led to improved survival and tumor regression without causing any systemic toxicity in melanoma and lung metastasis models. These findings suggest that mRNA encoding IL-12 in conjunction with STING agonists has the potential to confer superior clinical outcomes, representing a promising advancement in cancer immunotherapy.
研究领域:
癌症研究
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免疫学
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分子生物学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Ya Chu,Luyao Wang,Xi Huang,Cenxi Lao,Lin Luo,Jingyi Chen,Fangfei Jin,Lili Zhao,Kaiyuan Hu,Miao Lv,Xianjing Li,Yong Yang,Weijun Zhao,Wenguang Wang
The major challenge for in-situ cancer vaccines is to activate the DCs within the immunosuppressive tumor to initiate tumor-specific immune responses. By contrast, oncolytic viruses can always activate intratumoral DCs to initiate virus-specific immunity to eliminate viruses which will in turn reduce the anti-tumor effect of these viruses. To bridge the two approaches, we developed virus-mimicking nanoparticles (V-mimics) through self-assembly of artificial cyclic gadolinium-based GAMP (c·Gd·GAMP, a STING agonist), double-stranded RNA analog (Poly I: C), and indocyanine green (ICG). Within the V-mimics, c·Gd·GAMP and Poly I: C can simulate the DNA and RNA produced by virus replication to reverse the inhibition of the immunosuppressive tumor microenvironment on DCs by promoting the IFN-β secreting via activating nucleic acid sensors, thereby eliciting anti-tumor immune response in a manner akin to the immune response triggered by viruses. Notably, the V-mimics significantly promoted IFN-β secretion, enhanced DC maturation, and elicited robust tumor-specific immune memory when combined with photothermal therapy. In multiple tumor models, significant tumor inhibition was observed, including a metastasis and recurrence model. Therefore, leveraging the virus-mimicking particles to simulate the mechanism of virus-initiated specific immune responses to activate the intratumoral dendritic cells may open up new strategies for in-situ cancer vaccines.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2023
·
IF 19
Meng Wang,Xiaohui Zhang,Bing Liu,Chen Liu,Caimei Song,Yu Chen,Yubei Jin,Jing Lin,Peng Huang,Shaojun Xing
Post-surgical tumor recurrence remains a major clinical concern for patients with malignant solid tumors. Herein, an immunotherapeutic hydrogel (SA PBA /ZMC/ICG) is developed by incorporating metal ion-cyclic dinucleotide (CDN) nanoparticles (Zn-Mn-CDN, ZMC) and a photosensitizer (indocyanine green, ICG) into phenylboronic acid (PBA)-conjugated sodium alginate (SA PBA ) for photothermal therapy (PTT)-triggered in situ vaccination to inhibit post-surgical recurrence and metastasis of malignant tumors. The gelation of SA PBA /ZMC/ICG in the residual tumors can achieve accurate local PTT and the local sustained release of CDN and Mn 2+ with minimal detrimental off-target toxic effects. Furthermore, CDN, which is an agonist of the stimulator of interferon genes (STING), along with Mn 2+ can activate the STING pathway and trigger type-I-IFN-driven immune responses against tumors. Therefore, the immunotherapeutic hydrogel with enhanced immune response by STING agonist and PTT-induced immunogenic cell death (ICD) reprograms the post-surgical immunosuppressive microenvironment, substantially decreasing the post-surgical recurrence and metastasis of solid tumors in multiple murine tumor models when administered during surgical resection. Taken together, PTT-triggered and STING-mediated in situ cancer vaccination is an effective therapeutic intervention for post-surgical recurrence and metastasis of tumors.
研究领域:
肿瘤学
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免疫学
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生物材料学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）