Nature Cancer
·
2025
·
IF 28.5
Han Jinpeng,Wang Shenqiang,Fang Weifeng,Yang Yinxian,Zhou Ruyi,Zhang Yuqi,Yu Jicheng,Tang Ruikang,Liu Zhaoming,Gu Zhen
Long-acting controlled drug release formulations are highly desired for potentiating efficacy and reducing administration frequency. Here we present a kinetically controllable long-term interleukin-2 (IL-2) release platform by the fusion and boundary elimination of calcium carbonate and calcium phosphate amorphous phases. Unlike mixtures, a group of hybrid biominerals with the chemical formula Ca(CO 3 ) x (PO 4 ) 2(1− x )/3 (CaCPs, 0 < x < 1) was fabricated under high pressure (2 GPa), and the CaCPs showed crystallization-driven release behaviors to optimize the in vivo fate of IL-2. Ca(CO 3 ) 1/2 (PO 4 ) 1/3 dynamically remodeled immunosuppressive tumor microenvironments, preferentially activated cytotoxic and memory T cells by improving IL-2 redistribution and achieved weeks-long IL-2 retention in tumors with high tolerance and biosafety. In a melanoma model in female mice, Ca(CO 3 ) 1/2 (PO 4 ) 1/3 revealed superior antitumor effects to inhibit local tumor recurrence, hinder the growth of distant untreated tumors and maintain long-term T cell responses against the rechallenged metastatic tumors.
研究领域:
药学
·
免疫学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2026
·
IF 11
Minjiang Chen,Kun Zhang,Kai Li,Hui Xu,Jiayi Shi,Huilin Hu,Qianhui He,Liyun Zheng,Shiji Fang,Qiaoyou Weng,Min Xu,Zhongwei Zhao,Gaofeng Shu,Jiansong Ji
The acidic and immunosuppressive tumor microenvironment (TME) remarkably hampers the therapeutic efficacy of transcatheter arterial embolization (TAE) for hepatocellular carcinoma (HCC). Herein, uniform CaCO 3 nanoparticles encapsulated nickel–alginate microspheres (CaNPs/Ni-Alg MSs) were engineered using a microfluidic device, serving as an immune-regulated embolic agent to amplify TAE treatment of HCC. CaNPs/Ni-Alg MSs could adsorb His-tagged interleukin-2 (IL-2) and enable sustained release through coordination interactions between the His-tag and Ni 2 + , thereby reducing systemic cytokine elevation risk from IL-2 administration. IL-2-loaded microspheres (IL-2/CaNPs/Ni-Alg MSs) effectively neutralize intratumoral lactic acid (LA) via CaCO 3 , modulating the acidic TME. Proton neutralization restores IL-2 activity, enhancing T lymphocyte infiltration and proliferation. Additionally, lactate made available following acid neutralization may serve as a metabolic substrate, as supported by the calcium lactate and neutralization-mimicking experiments in vitro, contributing to CD8 + T-cell metabolic fitness. IL-2/CaNPs/Ni-Alg MSs could reprogram the TME into an immune-promoting milieu, synergizing with immune checkpoint blockade (ICB) therapy to suppress both primary and distant tumors. Not surprisingly, TAE with IL-2/CaNPs/Ni-Alg MSs combined with αPD-L1 achieved superior therapeutic efficacy without side effect in a rat orthotopic HCC model. Overall, this work presents a safe metabolism-reprogramming embolic strategy that repurposes LA to boost IL-2–mediated embolization-immunotherapy in HCC.
✓ 已验证
DOI
高影响因子
ACS Nano
·
2026
·
IF 17.3
Ping Li,Qianying Li,Lu Ding,Shiyu Peng,Hui Wei,Tingtao Chen,Yonghua Xiong,Ben Zhong Tang,Xiaolin Huang
Interleukin-2 (IL-2) immunotherapy offers considerable potential for metastatic cancers; however, its efficacy is limited by low response rates, dose-dependent toxicity, short half-life, poor tumor accumulation, and off-target immune activation. In this work, we present a biohybrid microrobot (IL-2@Z/C/A) engineered through biomimetic mineralization of IL-2 variant-secreting Escherichia coli Nissle 1917 (EcN) with a zeolitic imidazolate framework-8 (ZIF-8) shell coloaded with an aggregation-induced emission photosensitizer and catalase. The ZIF-8 coating preserves bacterial viability tumor-homing capability while preventing premature drug leakage and systemic exposure, thus minimizing off-target effects. Upon accumulation in the acidic tumor microenvironment (TME), the framework degrades to release engineered bacteria and therapeutic cargo. Locally delivered zinc ion release, light-triggered reactive oxygen species and EcN derived pathogen-associated molecular patterns act synergistically to induce Cle-caspase/GSDMD mediated pyroptosis, resulting in immunogenic cell death accompanied by damage-associated molecular pattern release and pro-inflammatory cytokine production. Simultaneously, catalase-driven oxygen generation alleviates hypoxia and suppresses HIF-1α-induced immunosuppression. In combination with PD-L1 blockade, IL-2@Z/C/A achieves near-complete tumor regression in a B16F10 melanoma model via a coordinated immune cascade: pyroptosis-mediated antigen exposure primes adaptive immunity, hypoxia reversal counteracts immunosuppression, and sustained local IL-2 release reverses T cell exhaustion, collectively reprogramming the immunosuppressive TME and eliciting strong antitumor immunity. This work establishes a distinct paradigm for spatially controlled immunotherapy and highlights the potential of this biohybrid microrobot in converting immunologically “cold” tumors into responsive niches.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL RESEARCH
·
2023
·Vol. 33
·期 12
·923-939
·
IF 44.1
Liu Rui,Zeng Lin-Wen,Li Hui-Fang,Shi Jun-Ge,Zhong Bo,Shu Hong-Bing,Li Shu
Combination therapy with PD-1 blockade and IL-2 substantially improves anti-tumor efficacy comparing to monotherapy. The underlying mechanisms responsible for the synergistic effects of the combination therapy remain enigmatic. Here we show that PD-1 ligation results in BATF-dependent transcriptional induction of the membrane-associated E3 ubiquitin ligase MARCH5, which mediates K27-linked polyubiquitination and lysosomal degradation of the common cytokine receptor γ chain (γ c ). PD-1 ligation also activates SHP2, which dephosphorylates γ c Y357 , leading to impairment of γ c family cytokine-triggered signaling. Conversely, PD-1 blockade restores γ c level and activity, thereby sensitizing CD8 + T cells to IL-2. We also identified Pitavastatin Calcium as an inhibitor of MARCH5, which combined with PD-1 blockade and IL-2 significantly improves the efficacy of anti-tumor immunotherapy in mice. Our findings uncover the mechanisms by which PD-1 signaling antagonizes γ c family cytokine-triggered immune activation and demonstrate that the underlying mechanisms can be exploited for increased efficacy of combination immunotherapy of cancer.
研究领域:
免疫学
·
肿瘤学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2026
·
IF 12.6
Fengkai Qiu,Xiaoxiao Chen,Qianhui He,Kai Li,Xinlong Chai,Shiji Fang,Fazong Wu,Dengke Zhang,Liyun Zheng,Zhongwei Zhao,Minjiang Chen,Jin Su,Jiansong Ji,Gaofeng Shu
Hepatocellular carcinoma (HCC) is commonly diagnosed at intermediate or advanced stages. While transcatheter arterial embolization (TAE) is the accepted locoregional therapy, embolization inevitably induces severe intratumoral hypoxia, leading to excessive lactate accumulation, metabolic reprogramming and the formation of an immunosuppressive tumor microenvironment (TME), factors that collectively limit durable therapeutic efficacy and promote tumor recurrence. Although immunotherapy has shown promise in HCC, the efficacy of combining TAE with immune-based strategies remains suboptimal, largely due to metabolic constraints and T cell dysfunction within the post-embolization TME. Interleukin-2 (IL-2) therapy can stimulate effector T cells but suffers from the drawbacks of systemic toxicity, a short half-life and TME-induced dysfunction. Recent evidence indicates that lactate-rich, acidic TMEs impair IL-2 stability and signaling, suppress CD8⁺ T cell function, and promote Treg cell activity, thereby further compromising IL-2-based immunotherapy following TAE. Here, we developed a nano-immunotherapy platform (Syr/IL-2@MPDA) using mesoporous polydopamine (MPDA) nanoparticles co-loaded with His-tagged IL-2 and the monocarboxylate transporter inhibitor Syrosingopine (Syr). Syr-mediated lactate regulation alleviates TME acidity and restores IL-2 activity, while MPDA enables mild photothermal therapy (mPTT) to transform immunologically "cold" tumors into "hot" phenotypes, thereby enhancing the immune response. This integrated strategy significantly enhanced antitumor immunity, achieving a tumor growth inhibition rate of 70.87% in a murine subcutaneous tumor model. In an orthotopic N1S1 HCC rat model, the treatment demonstrated strong therapeutic efficacy in combination with αPD-L1 and TAE, overcoming the hazards of TAE-induced lactate accumulation and immune suppression. Overall, this study demonstrates a safe and effective strategy that enhances IL-2 immunotherapy through mPTT and metabolic modulation, offering a promising combination treatment for advanced HCC.
✓ 已验证
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2023
·
IF 5.8
Jian Chen,Hui Wang,Li Zhang,Wanying Yan,Ruilong Sheng
Developing low-cost, easy-to-prepare, biocompatible and highly efficient vaccine carriers is a promising approach to realize practical cancer immunotherapy . In this study, through facile modification of mPEG5k-4-toluenesulfonate (mPEG5k-OTs) on PEI25k under mild conditions, a series of “stealth” mPEG5k-PEI25k polymers (PP1, PP2 and PP3) were prepared, their structures and physicochemical properties were characterized and theoretically analyzed. The polymers could bind/load ovalbumin (OVA) to form mPEG5k-PEI25k/OVA complexes as negatively charged nanoparticles with small hydrodynamic particle size (80–210 nm) and narrow size distribution. Compared to PEI25k/OVA, lower cytotoxicity could be achieved on mPEG5k-PEI25k/OVA complexes in dendritic cells (DCs). In DCs-RF 33.70 T-cells co-culture system, the mPEG5k-PEI25k/OVA complexes could bring about higher IL-2 production /secretion than that of PEI25k/OVA, notably, the optimum IL-2 secretion could reach 9.3-folds of the PEI25k/OVA under serum condition (10% FBS). Moreover, the cell biological features could be optimized by selecting suitable mPEG5k-grafting ratios and/or mPEG5k-PEI25k/OVA weight ratios. Intracellular imaging results showed that the mPEG5k-PEI25k(PP3)/Rhodamine-OVA complexes mainly localized inside lysosomes . Taken together, this work provided a facile method to prepare “stealth” PEGylated-PEI25k polymers with reduced cytotoxicity, promoted OVA cross-presentation efficiency and improved serum compatibility towards cancer immunotherapy.
研究领域:
生物医学工程
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Min Cai,Ruijuan Qi,Muqing Wang,Congyu Wu,Qian Chen,Yilin Guo,Yu Liu,Xin Huang,Yuan Gao,Yun Qi
DET decreases the transcription and translation of IL-2 in ConA-activated T cells. • DET inhibits ConA-activated NF-κB pathway, but fails to suppress MAPK signaling. • DET dampens ConA-induced nuclear translocation of NFAT. • DET directly suppresses calcineurin (CaN) activity not by reducing cytoplasmic Ca 2+ . • DET lowers serum IL-2 level of anti-CD3 antibody-treated mice. Deoxyelephantopin (DET) is a sesquiterpene lactone isolated from Elephantopus scaber , a traditional medicinal plant valued for its heat-clearing and detoxifying properties. As one of the major bioactive components, DET exhibits a variety of pharmacological activities, such as antitumor, antimicrobial, and anti-inflammatory effects. Nevertheless, its effect on T cell activation remains underexplored. Our study indicated that DET suppressed the proliferation and interleukin-2 (IL-2) production in T cells activated by various stimuli for T cell receptor (TCR)/CD3 signaling (i.e., concanavalin A (ConA), anti-CD3 antibody, and allogeneic major histocompatibility complex (MHC)). Mechanistically, DET lowered IL-2 mRNA level without affecting its stability in ConA-activated Jurkat T cells. Among three nuclear transcriptional pathways (mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), nuclear factor of activated T cells (NFAT)) triggered by ConA, DET did not suppress MAPK signaling, but significantly inhibited NF-κB activation by hindering inhibitor of kappa-B alpha (IκBα) phosphorylation and degradation, thereby preventing p65 nuclear translocation. Concurrently, DET could dampen the activation of NFAT signaling through inhibiting the activity of calcineurin (CaN) to impede NFAT nuclear translocation independent of decreasing cytoplasmic Ca 2+ (Ca 2+ [c] ). Unlike classical CaN inhibitors (CNIs), DET inhibits CaN activity without involving immunophilins. In vivo , DET could also reduce serum IL-2 level in acute T-cell activation mouse model induced by intravenous injection of anti-CD3 antibody. In conclusion, our findings reveal DET's dual mechanisms (NF-κB and NFAT inhibition) responsible for repressing IL-2 expression in the activated T cells, which may provide a promising candidate for the development of a novel IL-2 suppressive agent. Download: Download high-res image (270KB) Download: Download full-size image
✓ 已验证
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Dongyan Shao,Ting Bai,Bobo Zhu,Xiaojia Guo,Kai Dong,Junling Shi,Qingsheng Huang,Jie Kong
Natural killer (NK) cells have emerged as an important contributor to cancer immunotherapy, but their antitumor efficacy remains suboptimal. While cytokine-based priming shows promise in enhancing NK-cell activity, its clinical translation faces many challenges, including co-activation of multiple cytokines, poor pharmacokinetics, and limited mechanistic understanding. Here, we developed a polymeric micelle-based IL-15/IL-2 codelivery system (IL-15/2-PEG-PTMC) for NK-cell activation. In vivo studies demonstrated that the half-life of IL-15 and IL-2 as well as the recruitment of NK cell within tumor tissue was significantly increased after PEG-PTMC loading. Coupled with the coactivation effect of IL-15 and IL-2 conferred by this polymeric micelle-based system, it noticeably delayed the growth of tumors in mice compared to conventional NK cell activation approach, that was free IL-15 and IL-2. We also surprisingly found that cholesterol metabolism was highly involved in the NK cell activation by IL-15/2-PEG-PTMC. Following stimulation with IL-15/2-PEG-PTMC or IL-15, NK cells underwent a series of cholesterol metabolism reprogramming, which elevated the cholesterol levels on the NK cell membrane. This in turn promoted the formation of lipid rafts and actived immune synapse, effectively contributing to the enhancement of the NK cell's anti-tumor activity. We believe this will open a new avenue for improving the efficacy of NK cell immunotherapy by regulating cholesterol metabolism. This article is protected by copyright. All rights reserved
研究领域:
癌症生物学
·
免疫学
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
·
2019
·
IF 2.431
Chen-Jun Ye,Sheng-An Li,Yun Zhang,Wen-Hui Lee
Naturally occurring monoterpenes are known for their various pharmacological activities including anti-inflammation. K V 1.3 ion channel is a voltage-gated potassium channel and has been validated as a drug target for autoimmune and chronic inflammatory diseases like psoriasis . Here we experimentally test the direct interaction between monoterpenes and K V 1.3 ion channel. Our electrophysiological analysis determined that monoterpenes (geraniol, nerol , β-citronellol, citral and linalool) have inhibitory effects on K V 1.3 ion channel. Representatively, geraniol reversibly blocked K V 1.3 currents in a voltage-dependent manner with an IC 50 of 490.50 ± 1.04 μM at +40 mV in HEK293T cells. At the effective concentrations, geraniol also inhibited cytokine secretion of activated human T cells, including IL-2, TNF-α and IFN-γ. In an imiquimod-induced psoriasis-like animal model, geraniol administration significantly reduced psoriasis area and severity index scores, ameliorated the deteriorating histopathology and decreased the degree of splenomegaly . Together, our findings not only suggest that monoterpenes may serve as lead molecules for the development of K V 1.3 inhibitors, but also indicate that geraniol could be considered as a promising therapeutic candidate to treat autoimmune diseases.
研究领域:
药理学
·
免疫学
·
炎症研究
·
药物开发
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2020
·
IF 2.985
Min Liu,Yuan Meng,Leisheng Zhang,Zhongchao Han,Xiaoming Feng
Natural killer (NK) cells are pivotal effector lymphocytes characterized for the innate immune response to pathogenic microorganism and tumor cells without priming and sensitization. Despite emerging knowledge has highlighted the rosy prospects in tumor immunosurveillance , yet the large-scale clinical application of NK cell-based therapy is hindered largely attributes to the defects in generating sufficient and high-quality cellular products. Herein, on the basis of 16 kinds of candidate combinations, we investigated the feasibility of cytokine cocktail-based strategy for convenient and standardized NK cell cultivation as well as the multifaceted characteristics and cytotoxicity against tumor cells. Our results revealed that joint utilization of Interleukin (IL)-2, IL-15, IL-18 manifested the optimal facilitation upon the ex vivo expansion and proportion of NK cells in peripheral blood mononuclear cells (PBMCs). Meanwhile, the obtained NK cell population expressed high levels of activating molecules (CD16 and NKG2D) and exhibited splendid cytotoxicity against K562 cell line. Collectively, with the aid of cytokine-based programming, we established an alternative strategy for facilitating the large-scale persistence and activation of NK cells from peripheral blood, which would benefit the NK cell- and chimeric antigen receptor-modified NK (CAR-NK) cell-based autologous or allogeneic tumor immunotherapy.
研究领域:
免疫学
·
肿瘤学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2015
·
IF 4.074
Qing Zhang,Yi Xu,Sheng Zou,Xiaodan Zhang,Kun Cao,Qi Fan
The alkali-extractable polysaccharides (APMPs) were isolated from the water extracted residues of Radix Polygoni Multiflori, and further purified by DEAE-52 cellulose and Sephadex G-100 column chromatography to obtain a homogeneous polysaccharide (APMP-2) with molecular weights of 7724.8 Da. HPLC chromatography analysis identified that APMP-2 was a heteropolysaccharides and mainly composed of Galactose and Xylose with a molar ratio of 4.31: 1.06. It was shown that both APMP and APMP-2 were of activation effects on splenocytes and peritoneal macrophages, and also significantly restore the proliferation rate, phagocytic index and cytokine (IL-2 and TNF-α) production level of 5-FU-treated splenocytes/peritoneal macrophages in a dosage-dependent manner. The results suggested that polysaccharides presented in Radix Polygoni Multiflori water-extracted residues possessed immunomodulatory activity and could be used as potential immunomodulators, and this finding could be a reference for the utilization of Radix Polygoni Multiflori water extracted residues.
研究领域:
药理学
·
免疫学
·
植物化学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2018
·
IF 3.47
Yaser Gamallat,Xiaomeng Ren,Williams Walana,Abdo Meyiah,Ren Xinxiu,Yanyan Zhu,Meiqi Li,Siyuan Song,Luhan Xie,Yazeed Jamalat,Mohammad Zubair Saleem,Yufang Ma,Yi Xin,Dong Shang
Lactobacillus rhamnosus (LGG) is well documented strain with wide clinical applications. We investigated herein the possible protection role of LGG in against early preneoplastic colon carcinogenesis Aberrant crypt foci (ACF) in rat model. Sprague Dawley rats were pre-treated with or without LGG via oral gavage, followed by ACF induction with Dimethylhydrazine (DMH). LGG treated groups showed significant decrease in total number of ACF’s, and increased Bax, P53, and Caspase-3 proteins expression with significant attenuation of NFkB, Cox2 and β catenin expression compared to DMH group. Serum cytokines array revealed significant elevation of IL-2, IL-6, and IFN-γ, and attenuated level of IL-10 in LGG+DMH treated animals. Finally, the 16S rRNA fecal microbiome genomic analysis showed that LGG alters the gut microbiome structure, composition and functions at phylum, family and genus level. Collectively, LGG reduces colon ACFs incidence and multiplicity via inhibition of pro-carcinogenesis biomarkers and modulate the gut microbiome.
研究领域:
胃肠病学
·
微生物学
·
肿瘤学
·
分子生物学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）