CANCER LETTERS
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2026
·
IF 11.8
Ling-Dong Meng,Lu-Yang Jiang,Yang-Yang Liang,Zhan-Zhong Zheng,Qun Chen,Dan-Rui Li,Shuang Wang,Hao Yuan,Xu Feng,Kui-Rong Jiang
Pancreatic cancer has a dismal prognosis, largely due to resistance to all current therapeutic modalities, including prevailing immunotherapy. Deciphering the mechanisms underlying the immunosuppressive tumor microenvironment is pivotal for developing effective therapeutic strategies. In this study, we found that the expression of CCL20 is negatively correlated with the infiltration of CD8 + T cells, and consistently, patients with higher CCL20 expression have a worse prognosis. CCL20, as a secreted ligand protein regulated by SP5, can bind to its cognate receptor CCR6 in the tumor microenvironment and is mainly produced by tumor cells, as confirmed by single-cell RNA sequencing and immunofluorescence staining of tumor tissues. Compared with CCL20 wild-type tumors, CCL20 knockout tumors exhibited impaired growth, decreased infiltration of CCR6 + Tregs, and concomitantly increased infiltration of CD8 + T cells. Importantly, this altered immune infiltration phenotype was abolished in Treg-specific CCR6 knockout mice. Furthermore, CCR6 inhibition potentiated the efficacy of anti-PD1 immune checkpoint blockade. Taken together, our data demonstrate that tumor cell-derived CCL20 shapes an immunosuppressive microenvironment in pancreatic cancer by recruiting CCR6 + Tregs, suggesting that targeting the CCL20-CCR6 axis offers a promising therapeutic strategy, particularly when combined with immune checkpoint blockade.
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PubMed
高影响因子
Bioactive Materials
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2026
·
IF 23.6
Liang Song,Yongyuan Kang,Pai Peng,Qiaoxuan Wang,Shuqin Wang,Liyin Shen,Jinyue Zhang,Yang Zhu,Changyou Gao
Myocardial infarction (MI) disrupts immune homeostasis by impairing the recruitment and suppressive function of regulatory T cells (Tregs), which are hard to restore to date. In this study, a dual-functional platform based on core-shell microgels (Ab/HAPA C-S MGs) was developed to enhance Tregs homing and function within the post-infarct environment. The surface-modified C-C motif chemokine ligand 17 (CCL17) antibody neutralized excess CCL17, thereby enabling targeted Tregs recruitment. Propionic acid (PA) was released via hydrolytic cleavage of an encapsulated prodrug precursor (HAPA) within the core to promote Tregs immunosuppressive activity through fatty acid oxidation. The platform ensured localized retention and release of PA, addressing the pharmacokinetic limitations characteristic of short-chain fatty acid (SCFAs). The Ab/HAPA@C-S MGs enhanced Tregs recruitment by 4.2-fold through CCL17 neutralization, while enzymatically released PA boosted Tregs immunosuppression with 1.8-fold higher Foxp3 expression in vitro . In MI models, treatment with Ab/HAPA@C-S MGs promoted a 2.4-fold increase in Tregs infiltration while reducing Th17 cells in infarcted region, ultimately improving cardiac functions and attenuating myocardial fibrosis. These findings show potential of the SCFA-based C-S MGs system on regulating the immunomodulation and cardiac tissue repair.
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PubMed
高影响因子
Biomaterials Science
·
2020
·Vol. 8
·期 17
·4757-4766
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IF 6.183
Jing Zhang,Dan Liu,Jiale Liu,Yanfeng Han,Haiyan Xu,Xigang Leng,Deling Kong,Lanxia Liu
Combined blockades of CTLA-4 and PD-1 can yield better overall complementary clinical outcomes than individual blockades, but the response rates are still relatively low. To investigate the anti-tumor effects of various combined strategies, we designed various spherical nucleotide nanoparticles (SNPs) loaded with CTLA-4 aptamer (cSNPs), PD-1 siRNA (pSNPs) or both (hybrid SNPs, or hSNPs). The results demonstrated that hSNPs could promote significantly stronger anti-tumor immune responses in a nonredundant fashion than the mixture of pSNPs and cSNPs (pSNPs & cSNPs). We reasoned that this is because all individual immune cells could receive both CTLA-4 and PD-1 blockades when they engulfed hSNPs, but it is much less likely that individual immune cells could receive both CTLA-4 and PD-1 blockades as many of them may not take both pSNPs and cSNPS from pSNPs & cSNPs. Further results revealed that the synergistic immune stimulatory effects of CTLA-4 and PD-1 blockades in the form of hSNPs were at least partly through regulating the immune suppressive function of both Tregs and TIM3+ exhausted-like CD8 T cells and allowing effector T cells to expand. This mechanism is not identical to earlier reported mechanisms of CTLA-4 and PD-1 blockades.
研究领域:
癌症免疫治疗
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纳米技术
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分子生物学
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PubMed
高影响因子
CANCER CELL
·
2024
·
IF 48.8
Siyuan You,Shuqin Li,Lingsu Zeng,Jinsheng Song,Zifeng Li,Weiyun Li,Hengxiao Ni,Xu Xiao,Wenbo Deng,Hongye Li,Wenbo Lin,Chenyu Liang,Yanfei Zheng,Shih-Chin Cheng,Nengming Xiao,Mengsha Tong,Rongshan Yu,Jialiang Huang,Hongling Huang,Hongzhi Xu,Jiahuai Han,Jianlin Ren,Kairui Mao
The tumor microenvironment (TME) has a significant impact on tumor growth and immunotherapy efficacies. However, the precise cellular interactions and spatial organizations within the TME that drive these effects remain elusive. Using advanced multiplex imaging techniques, we have discovered that regulatory T cells (Tregs) accumulate around lymphatic vessels in the peripheral tumor stroma. This localized accumulation is facilitated by mature dendritic cells enriched in immunoregulatory molecules (mregDCs), which promote chemotaxis of Tregs, establishing a peri-lymphatic Treg-mregDC niche. Within this niche, mregDCs facilitate Treg activation, which in turn restrains the trafficking of tumor antigens to the draining mesenteric lymph nodes, thereby impeding the initiation of anti-tumor adaptive immune responses. Disrupting Treg recruitment to mregDCs inhibits tumor progression. Our study provides valuable insights into the organization of TME and how local crosstalk between lymphoid and myeloid cells suppresses anti-tumor immune responses.
研究领域:
免疫学
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肿瘤学
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细胞生物学
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高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Qiuxia Peng,Xiaolong Li,Chao Fang,Chunyan Zhu,Taixia Wang,Binxu Yin,Xiulin Dong,Huaijuan Guo,Yang Liu,Kun Zhang
Homeostasis and energy and substance metabolism reprogramming shape various tumor microenvironment to sustain cancer stemness, self-plasticity and treatment resistance. Aiming at them, a lipid-based pharmaceutical loaded with CaO 2 and glucose oxidase (GOx) (LipoCaO 2 /GOx, LCG) has been obtained to disrupt calcium homeostasis and interfere with glycometabolism. The loaded GOx can decompose glucose into H 2 O 2 and gluconic acid, thus competing with anaerobic glycolysis to hamper lactic acid (LA) secretion. The obtained gluconic acid further deprives CaO 2 to produce H 2 O 2 and release Ca 2+ , disrupting Ca 2+ homeostasis, which synergizes with GOx-mediated glycometabolism interference to deplete glutathione (GSH) and yield reactive oxygen species (ROS). Systematical experiments reveal that these sequential multifaceted events unlocked by Ca 2+ homeostasis disruption and glycometabolism interference, ROS production and LA inhibition, successfully enhance cancer immunogenic deaths of breast cancer cells, hamper regulatory T cells (Tregs) infiltration and promote CD8 + T recruitment, which receives a considerably-inhibited outcome against breast cancer progression. Collectively, this calcium homeostasis disruption glycometabolism interference strategy effectively combines ion interference therapy with starvation therapy to eventually evoke an effective anti-tumor immune environment, which represents in the field of biomedical research.
研究领域:
肿瘤学
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药学
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免疫学
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生物医学工程
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高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Qilin Li,Huiling Fan,Yunruo Xu,Miaodeng Liu,Jia Liu,Luming Xu,Meizhen Zou,Qian Cheng,Yan Zhang,Tao Liang,Lin Shi,Xianluo Hu,Lin Wang,Zheng Wang
Photothermal and photodynamic therapies (PTT and PDT) generating regional hyperpyrexia or reactive oxygen species (ROS) not only kill tumors within irradiated site, but also potentially suppress metastatic tumors far away from irradiated site by activation of antitumor immunity through inducing immunogenic cell death (ICD) (termed as “abscopal effect”). However, mono-PTT or mono-PDT are generally insufficient to produce intensive and long-lasting “abscopal effect”. Moreover, abundant immune suppressors within tumor microenvironment can offset ICD-induced antitumor effects that further cripple phototherapeutic efficacy. Towards effective eradication of both primary and metastatic tumors, it is necessary to combine photothermal and photodynamic antitumor effects as well as reverse immunosuppressive tumor microenvironment. Here, we report a hollow germanium nanosphere (HGNs) with both favorable photothermal and photodynamic effects. HGNs under near-infrared (NIR) irradiation generated hyperpyrexia and intracellular ROS, promoting ICD of tumor cells. Notably, HGNs-mediated photothermal and photodynamic effects reduce the expression of immunosuppressive indoleamine-2,3-dioxygenase (IDO), stemness- and invasion/migration-related genes. In preclinical tumor models, HGNs drives antitumor immunity by promoting effector T-cell infiltration and reducing immunosuppressive regulatory T cells (Tregs) under NIR, thus eradicating both primary and distant tumors along with extension of animal survival. Thus, with good biosafety, HGNs demonstrates a great clinically-translational potential.
研究领域:
癌症治疗
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纳米技术
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免疫疗法
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生物医学工程
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DOI
高影响因子
Journal of Advanced Research
·
2024
·
IF 11.4
Chunhua Huang,Cheng Lyu,Heung-Lam Mok,Yiqi Xu,Ka-Wing Cheng,Cheng Zhang,Die Hu,Lin Zhu,Chengyuan Lin,Xin Chen,Hor-Yue Tan,Zhaoxiang Bian
Introduction Ulcerative colitis (UC) is a chronic inflammatory disease characterized by loss of immune tolerance to luminal antigens and progressive intestinal tissue injury. Thus, the re-establishment of immune tolerance is crucial for suppressing aberrant immune responses and UC progression. Objectives This study aimed to investigate the mechanisms underlying the action of CDD-2103 and its bioactive compounds in mediating immune regulation in mouse models of colitis. Methods Two experimental colitis models, chronic 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and T-cell transfer-induced Rag1 -/- mice, were used to determine the effects of CDD-2103 on colitis progression. Single-cell transcriptome analysis was used to profile the immune landscape and its interactions after CDD-2103 treatment. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the major components interacting with lymphoid cells. A primary cell co-culture system was used to confirm the effects of bioactive component. Results CDD-2103 dose-dependently suppresses the progression of colitis induced by chemicals or T cell transplantation in Rag1 -/- mice. The effect of CDD-2103 is primarily attributable to an increase in the de novo generation of regulatory T cells (Tregs) in the lamina propria (LP). Single-cell transcriptomic analysis revealed that CDD-2103 treatment increased the number of tolerogenic dendritic cells (DCs). Mechanistically, CDD-2103 promoted tolerogenic DCs accumulation and function by upregulating several genes in the electron transport chain related to oxidative phosphorylation, leading to increased differentiation of Tregs. Further LC-MS analysis identified several compounds in CDD-2103, particularly those distributed within the mesenteric lymph nodes of mice. Subsequent studies revealed that palmatine and berberine promoted tolerogenic bone marrow-derived dendritic cells (BMDC)-mediated Treg differentiation. Conclusion Overall, our study demonstrated that the clinically beneficial effect of CDD-2103 in the treatment of UC is based on the induction of immune tolerance. In addition, this study supports berberine and palmatine as potential chemical entities in CDD-2103 that modulate immune tolerance.
研究领域:
免疫学
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药理学
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胃肠病学
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分子生物学
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细胞生物学
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PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Qingle Song,Guofang Zhang,Bo Wang,Guoli Cao,Dongjie Li,Yu Wang,Yuqian Zhang,Jin Geng,Hongchang Li,Yang Li
Although immuno-oncotherapy in clinic has gained great success, the immunosuppressive tumor microenvironment (TME) existing in the “cold” tumor with insufficient and exhausted lymphocytes may result in a lower-than-expected therapeutic efficiency. Therefore, a properly designed synergistic strategy that can effectively turn the “cold” tumor to “hot” should be considered to improve the therapeutic effects of immuno-oncotherapy. Herein, TME-responsive penetrating nanogels (NGs) were developed, which can improve the delivery and penetration of the co-loaded resiquimod (R848) and green tea catechin (EGCG) in tumors by a nano-sized controlled releasing system of the soluble cyclodextrin-drug inclusion complex. Consequently, the NGs effectively promoted the maturation of dendritic cells, stimulated the cytotoxic T lymphocytes (CTLs), and decreased the PD-L1 expression in tumors. The combination of NGs with the OX40 agonist (αOX40) further synergistically enhanced the activation and infiltration of CTLs into the deep tumor and inhibited the suppression effects from the regulatory T cells (Tregs). As a result, an increased ratio of active CTLs to Tregs in tumors (20.66-fold) was achieved with a 91.56% tumor suppression effect, indicating a successful switch of “cold” tumors to “hot” for an immunologically beneficial TME with significantly improved anti-tumor immune therapeutics. This strategy could be tailored to other immuno-oncotherapeutic approaches to solve the urgent efficiency concerns of the checkpoint-based treatment in clinic.
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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药学
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PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Wenhe Luo,Yanqiao Zeng,Qingle Song,Yu Wang,Feng Yuan,Qi Li,Yingnan Liu,Su Li,Nahar Jannatun,Guofang Zhang,Yang Li
Despite the success of immuno-oncology in clinical settings, the therapeutic efficacy is lower than the expectation due to the immunosuppressive inflammatory tumor microenvironment (TME) and the lack of functional lymphocytes caused by exhaustion. To enhance the efficacy of immuno-oncotherapy, a synergistic strategy should be used that can effectively improve the inflammatory TME and increase the tumor infiltration of cytotoxic T lymphocytes (CTLs). Herein, a TME hypoxia-responsive nanogel (NG) is developed to enhance the delivery and penetration of diacerein and (-)-epigallocatechin gallate (EGCG) in tumors. After systemic administration, diacerein effectively improves the tumor immunosuppressive condition through a reduction of MDSCs and Tregs in TME, and induces tumor cell apoptosis via the inhibition of IL-6/STAT3 signal pathway, realizing a strong antitumor effect. Additionally, EGCG can effectively inhibit the expression of PD-L1, restoring the tumor-killing function of CTLs. The infiltration of CTLs increases at the tumor site with activation of systemic immunity after the combination of TIM3 blockade therapy, ultimately resulting in a strong antitumor immune response. This study provides valuable insights for future research on eliciting effective antitumor immunity by suppressing adverse tumor inflammation. The feasible strategy proposed in this work may solve the urgent clinical concerns of the dissatisfactory checkpoint-based immuno-oncotherapy.
研究领域:
肿瘤学
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免疫学
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纳米技术
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药理学
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-21
·
IF 10.6
Chen Shang,He Yan,Huang Xin,Shen Yao,Zou Qingshuang,Yang Gun,Fu Li,Liu Quan,Luo Dixian
Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is challenging. In this study, a photosensitive, dual-targeting nanoparticle system (M.RGD@Cr-CTS-siYTHDF1 NPs) was developed. The structure includes a shell of DSPE-modified RGD peptides targeting integrin receptors on tumor cells and carboxymethyl mannose targeting CD206 receptors on macrophages, with a core of chitosan adsorbing m6A reading protein YTHDF1 siRNA and chromium nanoparticles (Cr NPs). The approach is specifically designed to target TAM and cancer cells, utilizing the photothermal effect of Cr NPs to disrupt the TME and deliver siYTHDF1 to TAM. In experiments with tumor-bearing mice, M.RGD@Cr-CTS-siYTHDF1 NPs, when exposed to laser irradiation, effectively killed tumor cells, disrupted the TME, delivered siYTHDF1 to TAMs, silenced the YTHDF1 gene, and shifted the STAT3-STAT1 equilibrium by reducing STAT3 and enhancing STAT1 expression. This reprogramming of TAMs towards an anti-tumor phenotype led to a pro-immunogenic TME state. The strategy also suppressed immunosuppressive IL-10 production, increased expression of immunostimulatory factors (IL-12 and IFN-γ), boosted CD8 + T cell infiltration and M1-type TAMs, and reduced Tregs and M2-type TAMs within the TME. In conclusion, the dual-targeting M.RGD@Cr-CTS-siYTHDF1 NPs, integrating dual-targeting capabilities with photothermal therapy (PTT) and RNA interference, offer a promising approach for molecular targeted cancer immunotherapy with potential for clinical application. Graphical Abstract
研究领域:
癌症生物学
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纳米技术
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免疫疗法
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分子生物学
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药理学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Xin Jiang,Zhengjie Huang,Zhuqing Liu,Sitong Wang,Yuyou Qiu,Xiaolian Su,Yitong Wang,He Xu
Immunotherapy has emerged as a revolutionizing therapeutic modality for cancer. However, its efficacy has been largely limited by a weak immune response and an immunosuppressive tumor microenvironment. Herein, we report a metal–organic framework (MOF)-derived titanium oxide nanoparticle (MCTx NP) as an immune booster that can greatly improve the immunotherapy efficacy by inducing “immunogenic cell death” (ICD) and remodeling the tumor microenvironment. The NPs, inheriting the characteristic structure of MIL-125 and enriched with oxygen vacancies (OVs), demonstrate both high photothermal conversion efficiency and a reactive oxygen species (ROS) generation yield upon near-infrared (NIR) activation. Moreover, the NPs can release O2 and reduce glutathione (GSH) in the tumor environment, showcasing their potential to reverse the immunosuppressive microenvironment. In vitro/vivo results demonstrate that MCTx NPs directly kill tumor cells and effectively eliminate primary tumors by exerting dual photodynamic/photothermal therapy under a single NIR irritation. At the same time, MCTx NPs augment the PD-L1 blockade efficacy by potently inducing ICDs and reversing the immunosuppressive tumor microenvironment, including promoting dendritic cell (DC) maturation, decreasing regulatory T cells (Tregs)’ infiltration, and increasing cytotoxic T lymphocytes (CTLs) and helper T cells (Ths), resulting in effective distant tumor suppression. This work highlights MCTx NP-mediated photodynamic- and photothermal-enhanced immunotherapy as an effective strategy for tumor treatment.
研究领域:
癌症研究
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纳米技术
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免疫学
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治疗学
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生物医学工程
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PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Yifu Lyu,Xiuyi Yang,Lei Yang,Jinyu Dai,Huanyu Qin,Yunuo Zhou,Yunan Huang,Yanmei Wang,Di Wu,Qindai Shuai,Qilong Li,Xiaofei Xin,Lifang Yin
Lipid nanoparticle-mediated co-delivery of siRNA and small molecule holds a great potential to treat metabolic dysfunction-associated steatotic liver disease (MASLD). However, targeted delivery of therapeutics to hepatocytes remains challenging. Taking the advantage of rising low density lipoprotein receptor/very-low density lipoprotein receptor (LDLR/VLDR) levels in MASLD, the biological fate of dinonylamine-ethylene glycol chlorophosphate-1-nonanol (DNNA-COP-NA) based lipid nanoparticles (LNPs) was oriented to liver tissues via apolipoprotein E (ApoE)-LDLR/VLDLR pathway. We then adopted a three-round screening strategy to optimize the formulation with both high potency and selectivity to deliver siRNA-HIF-1α (siHIF1α) and silibinin (SLB) payloads to hepatocytes. The optimized SLB/siHIF1α-LNPs mediates great siRNA delivery and transfection of hepatocytes. In high fat diet (HFD)- and carbon tetrachloride (CCl 4 )-induced mouse models of MASLD, SLB/siHIF1α-LNPs enabled the silencing of hypoxia inducible factor-1α (HIF-1α), a therapeutic target primarily expressed by hepatocytes, leading to significantly reduced inflammation and liver fibrosis synergized with SLB. Moreover, it is demonstrated the hepatocyte-targeting delivery of SLB/siHIF1α-LNPs has the potential to restore the immune homeostasis by modulating the population of Tregs and cytotoxic T cells in spleen. This proof-of-concept study enable siRNA and small molecule co-delivery to hepatocytes through intrinsic variation of targeting receptors for MASLD therapy.
研究领域:
药学
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分子生物学
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肝病学
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纳米技术
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PubMed
高影响因子
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