Cancer Communications
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2026
·
IF 28.4
Nianke Zang,Jinfeng Gan,Ye Chen,Zheng Huang,Chichu Xie,Junlong Dang,Changyuan Huang,Linjie Yang,Xuelian Chen,Guangli Rong,Jianbo Sun,Yiming Shao,Julie Wang,Guangying Qi,Yu Liu,Song Guo Zheng
Background: T-LAK cell-originated protein kinase (TOPK), a serine/threonine kinase, is aberrantly overexpressed in human tumors and promotes malignant proliferation. Melanoma is a highly immunogenic tumor in which CD8+ T cell-mediated cytotoxicity is usually less effective in tumor control and responsive to immune checkpoint blockade. It is unclear whether the expression and functional characterization of TOPK within the immune cells affect the tumor microenvironment (TME) in patients with melanoma. This study aims to elucidate the expression pattern and immunoregulatory function of TOPK in CD8+ T lymphocytes during antitumor responses. Methods: Public single-cell RNA-sequencing (scRNA-seq) dataset analysis and flow cytometry assessed TOPK in tumor-infiltrating CD8+ T cells from patients with melanoma. Genetic deletion and pharmacological inhibition of TOPK using HI-TOPK-032 tested T cell-mediated melanoma control. Flow cytometry and tumor cell coculture killing assays measured effector release and target-cell apoptosis. Mechanistic analyses included assessment of interferon regulatory factor 5 (IRF5) expression, together with combination therapy using a programmed cell death protein 1 (PD-1)-blocking antibody in vivo. scRNA-seq of tumor-infiltrating lymphocytes (TILs) from Topkfl/fl and Cd8CreTopkfl/fl mice was also performed to define TOPK-dependent immune programs within the melanoma TME. Results: Single-cell transcriptomes identified a TOPK+ subset of tumor-infiltrating CD8+ T cells in melanoma, which was higher than that in normal lymph nodes (LNs), and exhibited suppressed cytotoxic and cytokine programs. CD8+ T cell-specific Topk deletion increased granzyme B (GzmB), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) secretion and improved tumor control. TOPK-deficient CD8+ T cells showed elevated activation-associated signaling pathways and immune effector gene expression. In murine TIL scRNA-seq, Cd8CreTopkfl/fl tumors exhibited increased effector and activation programs, reduced exhaustion and dysfunction programs, and enhanced immune crosstalk in the TME. Mechanistically, TOPK suppressed IRF5 expression and HI-TOPK-032 restored CD8+ T cell cytotoxicity in vitro and, with anti-PD-1, further inhibited tumor growth and increased intratumoral cytokine production. In human CD8+ T cells, enforced TOPK expression impaired cytotoxicity and cytokine secretion, reversed by IRF5 coexpression. Conclusions: These findings establish TOPK as the immune checkpoint limiting CD8+ T cell functionality in tumors and indicate the potential of TOPK inhibition as a strategy to augment T cell-based immunotherapies.
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ACS Nano
·
2025
·
IF 16
Chang Yang,Qian Wu,Jiayi Liu,Xin Wang,Bo Pang,Rongbing Tang
Anti-CD47 therapy restores macrophage-mediated phagocytosis to reverse the tumor immunosuppressive microenvironment (TIME). However, peritumoral (PT) T cells, which play an indispensable role in tumor eradication, also rely on CD47 for maintenance. The potential impact of anti-CD47 therapy on their maintenance remains unclear. In this study, we reveal that anti-CD47 therapy induces the removal of PT T cells by macrophages, followed by a reduction in the replenishment of intratumoral T cells, although the therapy reinvigorates the TIME and establishes a favorable milieu for immune responses. To address this contradiction, we developed a magnetically responsive semilifeform by equipping E. coliminicell-CD47nb with a controllable separation cocoon composed of phase-change material and magnetic fluid. Under a constant magnetic field, the cocoon remains solid, shielding the anti-CD47 nanobody (CD47nb) and propelling the semilifeform to traverse PT regions without disturbing resident PT T cells. Upon reaching the tumor interior, an alternating magnetic field is applied to induce magnetic fluid heating, triggering a solid-to-liquid phase transition of the cocoon. The liquid-phase cocoon separates from the E. coliminicell-CD47nb, exposing CD47nb to reeducate the TIME. This semilifeform resolves the therapeutic paradox of anti-CD47 therapy by achieving spatiotemporal-controlled CD47 blockade and enhancing therapeutic efficacy in both primary and distant tumors.
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CELL RESEARCH
·
2025
·
IF 25.9
Qin Rui,Zhang Yong,Shi Jiawei,Wu Peng,An Chenyi,Li Zhenhai,Liu Nuo,Wan Ziyan,Hua Ting,Li Xiaolong,Lou Jizhong,Yin Weiwei,Chen Wei
Naturally evolved T-cell receptors (TCRs) exhibit remarkably high specificity in discriminating non-self antigens from self-antigens under dynamic biomechanical modulation. In contrast, engineered high-affinity TCRs often lose this specificity, leading to cross-reactivity with self-antigens and off-target toxicity. The underlying mechanism for this difference remains unclear. Our study reveals that natural TCRs exploit mechanical force to form optimal catch bonds with their cognate antigens. This process relies on a mechanically flexible TCR–pMHC binding interface, which enables force-enhanced CD8 coreceptor binding to MHC-α 1 α 2 domains through sequential conformational changes induced by force in both the MHC and CD8. Conversely, engineered high-affinity TCRs create rigid, tightly bound interfaces with cognate pMHCs of their parental TCRs. This rigidity prevents the force-induced conformational changes necessary for optimal catch-bond formation. Paradoxically, these high-affinity TCRs can form moderate catch bonds with non-stimulatory pMHCs of their parental TCRs, leading to off-target cross-reactivity and reduced specificity. We have also developed comprehensive force-dependent TCR–pMHC kinetics-function maps capable of distinguishing functional and non-functional TCR–pMHC pairs and identifying toxic, cross-reactive TCRs. These findings elucidate the mechano-chemical basis of the specificity of natural TCRs and highlight the critical role of CD8 in targeting cognate antigens. This work provides valuable insights for engineering TCRs with enhanced specificity and potency against non-self antigens, particularly for applications in cancer immunotherapy and infectious disease treatment, while minimizing the risk of self-antigen cross-reactivity.
研究领域:
免疫学
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细胞生物学
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生物力学
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2022
·
IF 5.714
Ruting Zheng,Miaomiao Kong,Siwei Wang,Bingqing He,Xin Xie
Multiple sclerosis (MS) is a chronic neuroinflammatory disease which causes demyelination, axonal damage and even disability. Th1 and Th17 cells , more precisely, the IFNγ/IL17a double producing CD4 + T cells, have been known to play critical roles in the pathogenesis of MS and EAE, a mouse model of MS. Polyamines not only regulate the immune system, but also are essential for the normal function of the central nervous system (CNS). In this study, we demonstrate that the supplementation of spermine (SPM), a biogenic polyamine, significantly suppresses EAE progression in both preventative and therapeutic ways. Further study suggests that spermine significantly reduces IFNγ + /IL17a - , IFNγ - /IL17a + and IFNγ + /IL17a + cells in periphery, and thus reducing the infiltration of these pathogenic cells into the CNS. In vitro , spermine has been shown to suppress the activation and proliferation of CD4 + T cells and also significantly impede the polarization of T effector cells in a dose-dependent manner, accompanied by the inhibition of ERK phosphorylation. Consistently, a number of MEK/ERK inhibitors (including PD0325901, FR180204 and selumetinib) have been found to mimic the effects of spermine in inhibiting CD4 + T cell activation and T effector cell differentiation. Collectively, spermine alleviates EAE progression by inhibiting CD4 + T cells activation and T effector cell differentiation in a MAPK/ERK–dependent manner, suggesting this pathway might be a target to develop effective therapies for MS.
研究领域:
免疫学
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神经科学
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药理学
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CELL
·
2026
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IF 45.1
Feng Li,Yuxing Hu,Yan Wang,Xiao Zhang,Shaowei Qiu,Xiaoming Hu,Wenjing Wang,Shuang Wang,Peilin Guo,Cui Song,Huaiji Wang,Changhao He,Jie Sun,Di Yu,Shuhua Yi,Jun Wei,Feifan Liu,Caopei Zheng,Jianxiang Wang,Yuhua Li,Guanghui Ma,Wei Wei
Although promising, chimeric antigen receptor T (CAR T) cell therapy for treating leukemias still faces the critical challenge of antigen modulation, which causes resistance. Building from our clinical insight that both diverse types of leukemia cells and corresponding CAR T cells strongly express CD71 (a ferritin receptor), we designed a ferritin aggregation cell engager (FACE) that can anchor to the CAR T cell surface, guide CAR T cells to face leukemia cells, and facilitate CAR recognition of cognate antigens. In vitro and in vivo experiments with diverse leukemia patient-derived cells and leukemia patient-derived xenograft models show that our FACE-CAR T cells succeed in enhancing therapeutic efficacy with good biosafety, lowering the antigen threshold for overcoming antigen modulation, and even loading chemodrugs in ferritin for combination therapy. This avidity engineering provides a neotype, facile, universal, and flexible approach for improving the efficacy of CAR T cell therapy for diverse refractory leukemias.
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Advanced Science
·
2023
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IF 15.1
Long Fang,Ruofei Zhang,Lin Shi,Jiaying Xie,Long Ma,Yili Yang,Xiyun Yan,Kelong Fan
The success of arsenic in degrading PML-RARα oncoprotein illustrates the great anti-leukemia value of inorganics. Inspired by this, the therapeutic effect of inorganic selenium on t(8; 21) leukemia is studied, which has shown promising anti-cancer effects on solid tumors. A leukemia-targeting selenium nanomedicine is rationally built with bioengineered protein nanocage and is demonstrated to be an effective epigenetic drug for inducing the differentiation of t(8;21) leukemia. The selenium drug significantly induces the differentiation of t(8;21) leukemia cells into more mature myeloid cells. Mechanistic analysis shows that the selenium is metabolized into bioactive forms in cells, which drives the degradation of the AML1-ETO oncoprotein by inhibiting histone deacetylases activity, resulting in the regulation of AML1-ETO target genes. The regulation results in a significant increase in the expression levels of myeloid differentiation transcription factors PU.1 and C/EBPα, and a significant decrease in the expression level of C-KIT protein, a member of the type III receptor tyrosine kinase family. This study demonstrates that this protein-nanocaged selenium is a potential therapeutic drug against t(8;21) leukemia through epigenetic regulation.
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ANALYTICAL SCIENCES
·
2018
·Vol. 34
·期 2
·149-153
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IF 1.355
Xiao Fang ZHANG,Hong Mei XU,Lei HAN,Nian Bing LI,Hong Qun LUO
The detection of disease-related DNA is of great significance for early and accurate diagnosis and therapy. In this work, we successfully achieved the sensitive detection of target DNA based on a thioflavin T (ThT)-induced G-quadruplex fluorescent biosensor. ThT, a water-soluble fluorescent dye, can induce G-rich sequences to form G-quadruplexes and obtain an obviously enhanced fluorescence. In this work, it was employed to construct a biosensor for the detection of HIV. When the target HIV existed, the hairpin DNA probes would be opened in succession and release the completely exposed G-rich sequence to combine with ThT. The simple and rapid biosensor performed satisfactory selectivity; it also exhibited sensitivity with a detection limit of 2.4 nM. With good performance in human serum, we believe that this optical biosensor has the potential to be applied to the practical detection of target DNA.
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Frontiers in Bioengineering and Biotechnology
·
2022
·
IF 6.064
Fangze Guo,Changqing Yuan,Hailin Huang,Xuyang Deng,Zirui Bian,Danyang Wang,Keke Dou,Li Mei,Qihui Zhou
Nano-hydroxyapatite (nHA) has been widely applied as a tissue-engineering biomaterial and interacted with osteoblasts/stem cells to repair bone defects. In addition, T cells that coexist with osteoblasts/stem cells in the bone modulate the regulation of osteoimmunology by cytokine formation. However, the effects of nHA on T cells and the following regulatory interplay on osteogenic differentiation have been rarely examined. In this work, the physicochemical properties of needle-like nHA are characterized by field emission scanning electron microscopy, zeta potential, Fourier transform-infrared and X-ray diffraction. It is found that as the concentration of nHA increases, the proliferation of T cells gradually increases, and the proportion of apoptotic T cells decreases. The percentage of CD4 + T cells is higher than that of CD8 + T cells under the regulation of needle-like nHA. Furthermore, the supernatant of T cells co-cultured with nHA significantly inhibits the osteogenic differentiation of MC3T3-E1 by downregulating the formation of alkaline phosphatase and calcium nodule compared with the supernatant of nHA. Thus, our findings provide new insight into the nHA-mediated T cell and osteoblast interactions.
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Biomass Conversion and Biorefinery
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2022
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IF 4.05
Liu Huiyu,Zhang Jun,Gu Jing,Yuan Haoran,Chen Yong
In the present study, a series of Ce-Zr binary metal oxides (Ce x Zr 1−x -T, x = 0.2, 0.5, 0.8) with variable physicochemical characteristics were developed for fast pyrolysis of cellulose, wherein thermal decomposition behaviors and kinetics were investigated using TG-MS and Py-GC/MS methods. Comprehensive characterizations including XRD, NH 3 -TPD, CO 2 -TPD, and SEM were conducted to unveil the essential structural properties of as-prepared Ce x Zr 1−x -T materials. Ce x Zr 1−x -T calcined at 450 °C and 550 °C could supply suitable medium to strong acid–base sites and good porosity for the pyrolysis of cellulose into ketones, aldehydes, and hydrocarbons, especially for Ce 0.8 Zr 0.2 –550. Elevation of heating rate and catalyst usage significantly promoted the yielding of ketones, aliphatic hydrocarbons, and aromatic hydrocarbons. Moreover, the activation energy for cellulose pyrolysis was lowered to 96.9 kJ/mol in the presence of Ce 0.8 Zr 0.2 –550, due to the promotional role of existing acid–base sites.
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INDUSTRIAL CROPS AND PRODUCTS
·
2021
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IF 5.645
Hui Guo,Jianwei Yu,Bingshuang Lei,Weiwei Ji,Huanhuan Liu,Bo Yin,Junqing Qian
As a kind of important natural compound with various physiological activities such as anti-oxidation, anti-inflammation, anti-aging, anti-cancer, anti-virus, etc, flavonoid had great application potential in food , cosmetics and pharmaceutical industries. However, the poor solubility limited their application. To solve this problem, one flavonoid glycoside , naringin , was esterified with lipase to improve its performance in the paper. Four fatty acids were selected as acyl donors to be esterified with naringin by single factor experiment, respectively. The results indicated that the optimal reaction conditions were the same: water activity was between 0.11 and 0.69, TLIM lipase was 50 mg/mL, acetone was used as the solvent, the molar ratio of substrate (naringin: fatty acid) was 1:10, and the substrates were first pretreated by ultrasound for 0.5 h, then reacted at 50 °C for 16 h. The conversion rates of naringin esterified with different fatty acids were all above 80.0%. Furtherly, the conversion rate of naringin was 93.9%, after the response surface experiment was carried out to optimize the lipase-catalyzed reaction conditions of naringin with palm oil. Lipophilicity and antioxidant ability of naringin esterified derivatives were measured. The results showed that the lipophilicity of naringin esterified derivatives was significantly higher than that of naringin. Although the free radical scavenging ability and reducing ability decreased by approximately 8% and 0.8%, respectively, the inhibiting oil peroxidation ability of naringin fatty acid esters were higher than that of naringin, which indicated that naringin esterified derivatives have the potential to become fat-soluble antioxidants.
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CATALYSIS TODAY
·
2021
·
IF 6.766
Lijie Pei,Jianxin Cao,Fei Liu,Anjie Yang,Mengqin Yao,Tianxiang Zhao,Xiaodan Wang,Sibudjing Kawi
The catalytic properties of bifunctional ZSM-5@t-ZrO 2 catalyst for methanol thiolation were revealed by using methanol and H 2 S as probe molecules. Taking the ZSM-5/t-ZrO 2 physically-blended catalyst, pure ZSM-5 and t-ZrO 2 as control catalysts, we investigated the characteristics of adsorption and transformation of different reaction molecules on or over different catalysts by combination of in-situ diffuse reflectance Fourier transform infrared spectroscopy (Drifts) and a variety of techniques including XRD, XPS, XRF, FT-IR, N 2 adsorption-desorption, CO 2 /NH 3 -TPD, and DSC. The results showed that the synergistic effect of acid sites between ZSM-5 phase and t-ZrO 2 phase in the bifunctional catalyst enhanced the adsorption and dissociation of methanol molecules, while the base sites in t-ZrO 2 phase were mainly responsible for the adsorption and dissociation of H 2 S molecules. Due to the small specific surface area of pure t-ZrO 2 catalyst, precursor species for sulfur deposition and carbon deposition were easily formed. Presulfurization could improve the initial activity of methanol thiolation and shorten the induction period. The dissociation of H 2 S at the base sites was the rate-determining step of the bimolecular reaction, and the appropriate increase of base sites in the bifunctional components could construct the matching formation rate of sulfhydryl and methoxy groups. At the same time, the special composite structure and meso-microporous system of ZSM-5@t-ZrO 2 could effectively reduce the formation rate of carbon and sulfur deposits.
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Micromachines
·
2022
·Vol. 14
·期 1
·45
·
IF 3.523
Zhou Lan,Yangcheng Lu
The combination of microstructural units is an effective strategy to improve the micromixing of liquid phase systems, especially viscous systems. However, how the microstructural combination influences micromixing is still not systematically investigated. In this work, the Villermaux/Dushman reaction is used to study the micromixing performance of the viscous system of the glycerol–water in the combination of a T-type micromixer and a micropacked bed. Micromixing performances under various structural parameters and fluid characteristics are determined and summarized, and the micromixing laws are revealed by dimensionless analysis considering the specific spatial characteristics and temporal sequence in the combined microstructures. It achieves good agreement with experimental results and enables guidance for the design and scaling-up of the combined T-type micromixer and micropacked bed towards micromixing intensification in viscous reaction systems.Keywords:micromixing;micropacked bed;microstructual combination;viscous system
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危险品化学品经营许可证（带存储）