STRUCTURE
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2024
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IF 4.4
Jian Sun,Xiangxiang Zhang,Liu Xue,Liang Cheng,Jing Zhang,Xin Chen,Zhirong Shen,Kang Li,Lai Wang,Chichi Huang,Jing Song
TIGIT is mainly expressed on T cells and is an inhibitory checkpoint receptor that binds to its ligand PVR in the tumor microenvironment. Anti-TIGIT monoclonal antibodies (mAbs) such as Ociperlimab and Tiragolumab block the TIGIT-PVR interaction and are in clinical development. However, the molecular blockade mechanism of these mAbs remains elusive. Here, we report the crystal structures of TIGIT in complex with Ociperlimab_Fab and Tiragolumab_Fab revealing that both mAbs bind TIGIT with a large steric clash with PVR. Furthermore, several critical epitopic residues are identified. Interestingly, the binding affinity of Ociperlimab toward TIGIT increases approximately 17-fold when lowering the pH from 7.4 to 6.0. Our structure shows a strong electrostatic interaction between ASP103 HCDR3 and HIS76 TIGIT explaining the pH-responsive mechanism of Ociperlimab. In contrast, Tiragolumab does not show an acidic pH-dependent binding enhancement. Our results provide valuable information that could help to improve the efficacy of therapeutic antibodies for cancer treatment.
研究领域:
免疫学
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结构生物学
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肿瘤学
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DOI
PubMed
高影响因子
Foods
·
2025
·Vol. 14
·期 24
·4323
·
IF 5.1
Yazhen Liu,Jiaqi Huang,Ji Yu,Luxin Fu,Ronglong Huang,Jing Liu,Bailin Deng,You-Bao Zhong,Duanyong Liu,Haimei Zhao
(1) Background: Ulcerative colitis (UC) is a persistent inflammatory condition of the intestine, characterized by dysregulated T cell-mediated immune responses. Curcumin (CUR), a common food additive and health supplement, is noted for possessing anti-inflammatory and immunomodulatory properties. Nevertheless, the molecular mechanisms underlying its therapeutic effects remain incompletely elucidated. This research aims to investigate the therapeutic mechanisms of CUR in UC, focusing on its role in restoring T cell homeostasis by modulating TIGIT and Neuropilin-1 (NRP1). (2) Methods: We employed a DSS-induced murine colitis model, combined with network pharmacology, molecular docking, protein–protein interaction docking, molecular dynamics simulations, andinvitroassays with Jurkat T cells. (3) Results: CUR markedly ameliorated clinical manifestations and histopathology in DSS-treated mice, restoring the balance of T cell and memory T cell subsets. Computational predictions and experimental validation showed that CUR downregulated TIGIT and NRP1 expression in inflamed colonic tissue and directly inhibited their expression in activated T cellsinvitro. (4) Conclusions: This study reveals a novel immunoregulatory mechanism of this natural compound. These findings suggest CUR modulates TIGIT/NRP1 to inhibit excessive T cell activation and restore immune homeostasis in UC.
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DOI
PubMed
高影响因子
BRITISH JOURNAL OF CANCER
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2025
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IF 6.8
Yu Huijuan,Jin Shaowen,Zeng Min,Yang Zhiqing,Wang Xiaofei
Background T-cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) is a checkpoint receptor thought to be involved in mediating T-cell exhaustion and dysfunction of natural killer (NK) cells in tumours and is emerging as novel promising targets in immunotherapy, however, the ligand binding and the efficacy of its antibody still need to be further explored. Methods Four different TIGIT antibodies in characteristics of antigen binding, in vitro effects on activated T cells, Fc region functions and tumour inhibition in animal models were compared. The antibody as monotherapy and combined with anti-PD-L1 antibody, effects on PBMC in ex vivo coculture with autologous human CRC organoids as well as PK profile were evaluated. Results Studies demonstrated that TIGIT antibody with PVR-competitive ability as monotherapy resulted in inhibition of tumour growth, sustained anti-tumour immune memory in tumour re-challenge mice, enhanced anti-tumour therapy in combination with anti-PD-L1. Ex vivo coculture assay suggested that TIGIT antibody treatment activated immune cells and promoted infiltration and tumour killing ability of autologous PBMC in human CRC organoids. Conclusions Our study broadens the knowledge of TIGIT antibody in cancer immunotherapy and may benefit future development of next-generation checkpoint inhibitors with improved clinical outcomes.
研究领域:
肿瘤免疫学
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分子生物学
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药物研发
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DOI
PubMed
高影响因子
Applied Materials Today
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2024
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IF 7.2
Xi Wang,Yu Wang,Qihang Zhao,Zhenchu Feng,Qingyi Liu,Gang Wang,Jiakui Zheng,Lin Tao,Jianguo Zhang,Xi Chen
Photothermal immunotherapy, especially combined with immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1), marks a breakthrough in cancer treatment. However, therapy often triggers compensatory upregulation of other immune checkpoints. This study introduces an advanced strategy to enhance the efficacy of photothermal immunotherapy by utilizing a novel nanocarrier that targets both PD-1 and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) immune checkpoints. The dual blockade could counteract the compensatory upregulation of immune checkpoints triggered by PD-1 targeted therapies alone. The nanocarrier of this work is composed of a ZrB 2 photothermal core and a mesoporous silica layer, and finally coated with biocompatible polydopamine. This design could effectively deliver both TIGIT and PD-1 inhibitors directly to tumor sites, minimizing systemic side effects such as cytokine release syndrome. We demonstrate that this approach not only enhances cytotoxic responses of T and NK cells, but also promotes macrophage polarization towards a tumor-suppressing M1 phenotype dendritic cell maturation and immunogenic cell death. Our findings provide a promising avenue for cancer immunotherapy.
研究领域:
癌症免疫治疗
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纳米技术
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免疫学
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肿瘤学
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DOI
高影响因子
ADVANCED FUNCTIONAL MATERIALS
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2024
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IF 18.5
Tian Tian,Jingguo Wang,Weitao Wang,Haitao Wu,Qianhui Li,Fei Wang,Hua Wang,Zhengbao Zha
Drawing inspiration from recent advances in microwave ablation (MWA) induced in situ tumor vaccination, a colloidal hydrogel comprising amphoteric gelatin nanoparticles and poly (acrylic acid) (PAA)-calcium carbonate nanorods (PAA-CaCO 3 NRs) is developed to deliver the microwave-sensitive agent sodium fluoride (NaF) which can also act as a glycolysis inhibitor in conjunction with the blockade of the T-cell Ig and ITIM domain (TIGIT), a coinhibitory receptor expressed by both natural killer (NK) cells and T cells. The combination of NaF with microwave (MW) thermal-dynamic sensitization effectively reversed the acidic and immunosuppressive tumor microenvironment (TME). Moreover, the incorporation of anti-TIGIT monoclonal antibody (aTIGIT) molecules amplified both the innate and adaptive immune responses by counteracting the exhaustion of NK and effective CD8 + T cells. This augmentation resulted in enhanced tumor elimination and suppression of tumor metastasis and recurrence. Thus, this study underscores the potential of colloidal hydrogel-sensitized MWA therapy, in conjunction with aTIGIT treatments, as a promising clinical strategy for in situ cancer vaccination.
研究领域:
肿瘤学
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生物医学工程
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免疫学
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DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·759
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IF 12.6
Wang Jia,Wang Zhiji,Li Kaiming,Liu Yue,Tang Chunming,Gao Huimin,Zhou Yupeng,Wang Pengpeng,Wu Haisi,Liu Pengfei,Xu Huae,Li Xiaolin
The clinical therapeutic effect of immune-checkpoint blockade (ICB) on triple-negative breast cancer (TNBC) is limited due to low tumor immunogenicity and tumor immunosuppressive microenvironment. Combination therapies of chemotherapy and ICB have been confirmed efficacious. Herein, poly(L-lysine) dendrimer (PLLD) nanosphere (PR-T@PLLD) integrating chemotherapeutic drug paclitaxel (PTX), natural anti-tumor compound Rubioncolin C (RC) and TIGIT/PVR blocking peptide D TBP-3 is constructed for chemo-immunotherapy of anti-PD-1 resistant tumor. The PEGylation and D TBP-3 modification endow PR-T@PLLD with prolonged blood circulation, enhanced tumor penetration and improved internalization. In the acidic environment of lysosomes, PR-T@PLLD disassembles and releases PTX, RC and D TBP-PLLD. The cell death induced by PTX is significantly enhanced through synergy with RC. RC collaborated PTX also triggers robust immunogenic cell death that efficiently increases tumor infiltration of cytotoxic T lymphocytes (CTLs). Additionally, the released D TBP-PLLD inhibits the exhaustion of CTLs via directly binding to TIGIT and blocking the interaction of TIGIT with its ligand PVR. Thus, PR-T@PLLD arouses a conspicuous anti-tumor immune response via increasing income and reducing expenditure of CTLs. Moreover, PR-T@PLLD reduces the recruitment of immunosuppressive cells in tumor. PR-T@PLLD also inhibits tumor metastasis through evoking immune memory response and inhibiting epithelial-mesenchymal transition and extracellular matrix degradation. In general, PR-T@PLLD is a promising nanoplatform realizing synergistic enhancement of chemo-immunotherapy against anti-PD-1 resistant TNBC. Graphical
研究领域:
纳米医学
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癌症免疫治疗
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药物递送系统
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分子肿瘤学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
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2024
·Vol. 15
·期 1
·1-16
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IF 14.7
Ye Qian-Ni,Zhu Long,Liang Jie,Zhao Dong-Kun,Tian Tai-Yu,Fan Ya-Nan,Ye Si-Yi,Liu Hua,Huang Xiao-Yi,Cao Zhi-Ting,Shen Song,Wang Jun
The functions of natural killer (NK) and T cells in innate and adaptive immunity, as well as their functions in tumor eradication, are complementary and intertwined. Here we show that utilization of multi-specific antibodies or nano-antibodies capable of simultaneously targeting both NK and T cells could be a valuable approach in cancer immunotherapy. Here, we introduce a tri-specific Nano-Antibody (Tri-NAb), generated by immobilizing three types of monoclonal antibodies (mAbs), using an optimized albumin/polyester composite nanoparticle conjugated with anti-Fc antibody. This Tri-NAb, targeting PDL1, 4-1BB, and NKG2A (or TIGIT) simultaneously, effectively binds to NK and CD8 + T cells, triggering their activation and proliferation, while facilitating their interaction with tumor cells, thereby inducing efficient tumor killing. Importantly, the antitumor efficacy of Tri-NAb is validated in multiple models, including patient-derived tumor organoids and humanized mice, highlighting the translational potential of NK and T cell co-targeting.
研究领域:
免疫学
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肿瘤学
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生物技术
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分子生物学
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DOI
PubMed
高影响因子
MOLECULAR THERAPY
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2024
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IF 12.1
Xiaozhen Kang,Yifeng Han,Mengdi Wu,Yuxin Li,Peng Qian,Chuning Xu,Zhengyun Zou,Jie Dong,Jiwu Wei
Tumor necrosis factor (TNF) has been recognized as an immune activation factor in tumor immunotherapy. Our study demonstrated that TNF blockade markedly enhanced the antitumor efficacy of oncolytic adenovirus (AdV) therapy. To minimize systemic side effects, we engineered a recombinant oncolytic AdV encoding a TNF inhibitor (AdV-TNFi) to confine TNF blockade within the tumor microenvironment (TME). AdV-TNFi significantly improved therapeutic outcomes across various solid tumor models, including four murine and two golden hamster cancers. Immune cell profiling identified CD8 + T cells as the primary mediators of AdV-TNFi-induced antitumor effects, rather than CD4 + T or NK cells. Additionally, AdV-TNFi significantly decreased the infiltration of suppressive myeloid-derived immune cells within the TME and promoted long-term antitumor immune surveillance. Further investigation indicated that TNFR2, more than TNFR1, is pertinent to the immunosuppressive TME, with a recombinant AdV-encoding anti-TNFR2 demonstrating comparable antitumor efficacy to AdV-TNFi. Moreover, AdV-TNFi enhanced the antitumor efficacy of gemcitabine and immune checkpoint blockades (ICBs), such as anti-PD-L1 and anti-TIGIT antibodies, in pancreatic carcinoma and the anti-EGFR antibody in colon carcinoma. In conclusion, intratumoral blockade of the TNF/TNFR2 axis using AdV augments cancer immunotherapy efficacy while mitigating the risks associated with systemic TNF or TNFR2 suppression, warranting further clinical investigation.
研究领域:
肿瘤学
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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
ACS Nano
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2024
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IF 15.8
Yongkang Yu,Fan Zhang,Wenqing Xiao,Qinzhen Cheng,Tingxuan Li,Jing Tang,Wei Tao,Lin Mei
Chemotherapy is currently a widely used treatment for cancer in clinical settings. Some chemotherapeutic drugs such as oxaliplatin (OXA) can cause tumor immunogenic cell death (ICD), activate immunity, and realize chemoimmunotherapy for tumors. However, the low degree of accumulation and immunosuppressive microenvironment in tumors limit the immunotherapeutic efficacy of these drugs. T cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor (PVR) is an inhibitory immune checkpoint pathway involved in mediating natural killer (NK) cell and T cell exhaustion in tumors. TIGIT expression is up-regulated in NK cells and CD8+ T cells during tumor development. Moreover, we first found that tumors upregulated PVR expression after OXA treatment in previous work. Here, we systematically analyzed the effects of OXA on the TIGIT/PVR pathway, further proving the effectiveness of the combination of OXA and TIGIT/PVR blocking combination. We developed engineered TIGIT-expressing cell membrane nanovesicles loaded with OXA (OXA@TIGIT MVs) for synergistic cancer therapy. OXA@TIGIT showed good efficacy in several cancer models, leading to tumor regression, effectively inhibiting tumor growth and prolonging mouse survival. Furthermore, the OXA@TIGIT MVs activate a strong tumor-specific immune response in the body, providing long-term (more than 2 months) protection from tumor reactivation in the B16F10 melanoma rechallenge mouse model.
研究领域:
癌症生物学
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免疫学
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药理学
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纳米技术
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Small
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2025
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IF 12.1
Weitao Wang,Haitao Wu,Xuan Zhang,Yang Hong,Shi Tao,Xiangjing Cao,Shipeng Wang,Lisha Zha,Zhengbao Zha
Using entire tumor cells or tissues that display both common and patient-specific antigens can potentially trigger a comprehensive and long-lasting anti-tumor immune response. However, the limited immunogenicity, low uptake efficiency, and susceptibility to degradation of whole-component antigens present significant challenges. In this study, we employed tumor lysates (TLs) as whole-component antigens, in conjunction with MgAl-layered double hydroxide (MA) as nanoadjuvants and Mn 2+ as immunostimulants, to create personalized MMAT (Mn 2+ -MA-TLs) nanovaccines. After subcutaneous injection of MMAT nanovaccines, the high local concentrations of TLs and Mn 2+ facilitated the recruitment and activation of antigen-presenting cells (APCs), thereby inducing a robust adaptive immune response. Remarkably, MMAT nanovaccines enabled lysosomal escape, enhanced antigen cross-presentation, and activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in APCs. Furthermore, MMAT nanovaccines, when combined with the anti-TIGIT monoclonal antibody (aTIGIT), an immune checkpoint inhibitor, not only stimulated T-cell-based adaptive anti-tumor immune responses but also activated the NK-cell-based innate anti-tumor immunity, effectively suppressing tumor growth, recurrence, and metastasis. Thus, the ternary MMAT nanovaccines developed here introduced a pioneered paradigm for the rapid preparation of whole-component tumor antigens with nanoadjuvants and immunostimulants into nanovaccines, offering new prospects for clinical immunotherapies.
研究领域:
癌症免疫疗法
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免疫学
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纳米医学
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肿瘤生物学
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产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2024
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IF 5.4
Shichao Zhang,Yijiang Liu,Yuhan Xie,Chenchun Ding,Renjie Zuo,Zhenzhen Guo,Shiyong Qi,Tingting Fu,Weibin Chen
Breast cancer represents a substantial contributor to mortality rates among women with cancer. Chemical dynamic therapy is a promising anticancer strategy that utilizes the Fenton reaction to transform naturally occurring hydrogen peroxide (H2O2) into hydroxyl radicals (•OH). Additionally, cancer immunotherapy using immune drugs, such as imiquimod (R837), has shown promise in activating T cells to kill tumor cells. In this study, we proposed a Fe3O4@R837 smart nanoplatform that can trigger the Fenton reaction and induce immune responses in breast cancer treatment. Furthermore, we performed transcriptome sequencing on breast cancer samples and used the R package (limma) to analyze differential expression profiles and select differentially expressed genes (DEGs). We obtained clinical information and RNA expression matrix data from The Cancer Genome Atlas database to perform survival analysis and identify prognostic-related genes (PRGs) and molecular subtypes with distinct prognoses. We used the TIMER 2.0 web and other methods to determine the tumor immune microenvironment and immune status of different prognostic subtypes. We identified DPGs by taking the intersection of DEGs and PRGs and performed functional analyses, including gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis, to elucidate potential mechanisms. Subsequently, we constructed a protein–protein interaction network using the STRING database to visualize the interactions between the DPGs. We screened hub genes from the DPGs using the Cytoscape plugin and identified six hub genes: CD3E, GZMK, CD27, SH2D1A, ZAP70, and TIGIT. Our results indicate that these six key genes regulate immune cell recruitment to increase T-cell cytotoxicity and kill tumors. Targeting these key genes can enhance immunotherapy and improve the breast cancer prognosis.
研究领域:
癌症生物学
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分子生物学
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免疫学
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生物信息学
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基因组学
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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）