ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Zhen-Ming Lu,Zi-Wen Qiu,Yan-Mei Li,Ke-Yan Zhang,Ye-Yang Wu,Ni Yan,Hong Cheng
Breast cancer cells are characterized by heightened autophagy, which impairs tumor-associated antigen presentation and represents a significant barrier to the antitumor immunity. In this study, a PD-L1-targeting autophagy modulator (PFC@CQ) is fabricated to activate the photoimmunotherapy against breast cancer. Specifically, the hydrophobic photosensitizer protoporphyrin IX (PpIX) is covalently linked to the hydrophobic peptide FFVLK and a PD-L1-targeting peptide sequence CLQKTPKQC, resulting in the formation of an amphiphilic photosensitizer-peptide conjugate (PpIX-FFVLK-CLQKTPKQC, called PFC), which is capable of encapsulating the autophagy inhibitor chloroquine (CQ). PFC@CQ can not only facilitate the targeted drug codelivery to PD-L1-overexpressing breast cancer cells, but also effectively disrupt their immune evasion by blocking PD-1/PD-L1 pathway. Upon light irradiation, the photodynamic therapy (PDT) of PFC@CQ induces tumor cell destruction and immunogenic cell death (ICD), causing the release of damage-associated molecular patterns (DAMPs). Simultaneously, PFC@CQ can inhibit autophagy pathway to mediate the upregulation of MHC-I, thereby enhancing antigen presentation. This cascade immunomodulation promotes the dendritic cell maturation and CD8+ T cell activation, leading to a synergistic suppression of both primary and metastatic tumors. This work introduces an innovative autophagy modulation strategy with potent immunomodulatory capability, demonstrating a potential to trigger systemic antitumor immune responses through local treatment.
研究领域:
肿瘤学
·
免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
Huimin Xie,Lin Ma,Xiaoli He,Songsong Zhao,Jin Wang,Ao Zhu,Changming Liu,Olga Piskareva,Chao Deng,Fenghua Meng,Mi Liu
Introduction: Cancer vaccines work through activating tumor-specific T cells, which can specifically attack cancer cells by recognizing antigens binding with Major-Histocompatibility-Complex I (MHC I) molecules. The downregulation or loss of MHC I expression on tumor cells can affect the efficacy of cancer vaccines.Methods: Herein, to increase the MHC I expression on tumor cells, a nanovesicle-based strategy was developed to improve the efficacy of cancer vaccines. Several clinically applied medicines, such as tyrosine kinase inhibitors (TKIs), were screened for their capacity to upregulate MHC I.Results: Two TKIs, Sunitinib and Sorafenib, were found to be very effective in elevating MHC I expression, and they were encapsulated into redox-responsive nanovesicles respectively (SUN-KD10 or SOR-KD10), which demonstrated favourable tumor-targeting capabilities in the tumor microenvironment. Sunitinib or Sorafenib activates the IFNγ/STAT1 pathway, which improve the expression of MHC I. When combined with whole-tumor-antigen-loaded nanovaccines, these nanovesicle formulations elicited a synergistic antitumor effect in both breast cancer and melanoma mouse models. The tumors in the tumor-bearing mice treated with combined strategy grew more slowly and the survival times of such mice are significantly prolonged.Discussion: The studies demonstrated that more tumor-specific T cells were activated in the combined strategy treated mice, suggesting improved immune-mediated tumor clearance. This combinatorial approach provides a promising strategy to overcome immune evasion and to enhance the therapeutic outcomes of cancer vaccine-based immunotherapy by using clinical-applied medicines with cancer vaccines.
研究领域:
肿瘤学
·
免疫学
·
纳米技术
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2020
·
IF 4.389
Mengyue Pei,Rong Xu,Chuangnian Zhang,Xiaoli Wang,Chen Li,Yunzhang Hu
Cancer immunotherapy is an important tumor therapy option for prevention and treatment of tumors and has attracted tremendous interests. However, the therapeutic outcomes are limited by insufficient antigen uptake and presentation by antigen-presenting cells such as dendritic cells (DCs). In this study, mannose-functionalized antigen nanoparticles with endosome escape activity were designed for targeted DCs, accelerated endosomal escape and enhanced MHC-I antigen presentation for cancer immunotherapy. Mannose was selected as DCs targeting ligand to enhance antigen uptake. Model antigen ovalbumin (OVA) was directly conjugated with mannose to obtain DCs targeting antigen, which was then complexed with polyethylenimine (PEI) through electrostatic interaction to form mannose-functionalized antigen nanoparticles (MAN-OVA/PEI NPs). Flow cytometry analysis revealed that the MAN-OVA/PEI NPs greatly increased antigen uptake by DCs compared with OVA/PEI NPs. Confocal laser scanning microscopy further demonstrated that MAN-OVA/PEI NPs enhanced cytosolic antigen release. Moreover, MAN-OVA/PEI NPs significantly promoted cytokine production and DCs maturation in vitro . More importantly, MAN-OVA/PEI NPs treated DCs exhibited enhanced cross-presentation to B3Z T cell hybridoma in vitro . This work suggests that mannose-functionalized antigen nanoparticles provide a versatile delivery vehicle for targeted DCs, accelerated endosomal escape and enhanced MHC-I antigen presentation for cancer immunotherapy.
研究领域:
癌症免疫治疗
·
纳米技术
·
免疫学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal for ImmunoTherapy of Cancer
·
2025
·Vol. 13
·期 9
·e011893
·
IF 10.6
Zhengning Yang,Zhongxuan Meng,Shangyuan Liu,Yuxin Chen,Xuhong Gan,Zi‑Mei Zhang,Xiaoshan Luo,Jiahong Yan,Huijin Chen,Danqing Huang,Lihong Huang,Xiaomin Zeng,Wenyu Ma,Jun Liu,Linlin Wang,Haotian Huang,Xinyi Yang,Mei Hu,Lin Chen,Hongli Du,Qibin Leng,Li Qiu,Xiaoling Wang
Background Nonsense-mediated messenger RNA decay (NMD) is a highly conserved surveillance system that degrades mRNAs with premature termination codons (PTCs), and regulates the mRNA quantity. Cancer cells hijack NMD to compensate for the imbalanced DNA levels and modulate their antigenicity. We identified the LTO1/YAE1 complex as NMD factors regulating ribosome biogenesis. Our study aimed to investigate their roles in modulating NMD and major histocompatibility complex class I (MHC-I) antigen presentation, which is vital for cancer immunotherapy. Methods Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated protein 9 (Cas9)-mediated gene knockouts, overexpression, and mutational analysis were used to explore the role of LTO1 and YAE1 in NMD and MHC-I expression across various tumor cell lines, assayed by fluorescent reporter-based assays, fluorescence-activated cell sorting analysis, reverse transcription-quantitative PCR, mRNA decay assay, and polysome profiling. Transcriptomic analyses were used to assess the expression of LTO1/YAE1 and their correlation with MHC-I molecules in human cancers. T cell receptor (TCR)-T cells and tumor cells coculture were employed to monitor the effect of LTO1 and YAE1 loss on T cell activation. Iron chelators were further tested as NMD inhibitors to enhance cancer immunotherapy using in vitro coculture assay and a mouse tumor model for immune checkpoint blockade (ICB) therapy. Results We demonstrate that deficiency in LTO1, YAE1, or their downstream target ABCE1 impairs NMD, causes the overexpression of key regulators of MHC-I, including NLR family CARD domain containing 5 (NLRC5), interferon regulatory factor 1 (IRF1), and nuclear factor-kappa B (NFκB), which results in enhanced T cell activation and tumor cell killing in TCR-T models. Transcriptomic analyses reveal that the LTO1/YAE1 complex is frequently overexpressed in human cancers, where it negatively regulates MHC-I. Moreover, low doses of iron chelators inhibit NMD and enhance MHC-I expression, leading to improved recognition and activation of CD8 + T cells, thereby promoting antigen-specific killing and increasing the efficacy of TCR-T and ICB therapy. Conclusions Collectively, our findings establish novel roles for the LTO1/YAE1 complex in regulating MHC-I expression via NMD. As MHC-I is crucial for antigen presentation and T cell activation, these results reveal a previously unappreciated link between NMD and tumor immunogenicity, with potential implications for cancer immunotherapies.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2026
·
IF 11
Shanlingzi Huang,Lu Gao,Yujun Chen,Zhaoming Fu,Ziyou Wang,Yifan Liu,Zhicheng Zhou,Ru Huang,Wen Song,Feifan Zhou
Triple-negative breast cancer (TNBC), characterized by low immunogenicity, is a challenging issue in clinical treatment due to its poor response to various therapies. The transformation of TNBC from a “cold tumor” with low immunogenicity into a “hot tumor” that elicits stronger immune responses is a key research focus. Photodynamic therapy (PDT) has emerged as a promising solution for TNBC treatment because it can effectively induce immunogenic cell death (ICD), which prompts the release of damage-associated molecular patterns (DAMPs) and activates immune responses. The role of MHC-I molecules in antigen presentation is crucial, but TNBC cells often evade immune surveillance by downregulating or losing MHC-I expression. Recent studies have shown that inhibiting the activity of complex II (CII) in the mitochondrial electron transport chain of tumor cells can promote MHC-I expression. Based on this finding, the combination of the PDT photosensitizer PCN-224 with the CII inhibitor 3-nitropropionic acid (3NPA) to form PCN@3NPA has been innovatively developed. Furthermore, modification with hyaluronic acid (HA) enables targeted delivery to TNBC cells that overexpress CD44. PDT induces ICD in tumor cells, releasing large amounts of DAMPs, while the sustained release of 3NPA effectively inhibits CII activity, significantly enhances MHC-I expression, thereby boosting tumor cell immunogenicity. This process significantly improves the recognition and killing of tumor cells by CD8 + T cells, markedly strengthening the body's anti-tumor immune response. This approach offers a novel and promising strategy for efficiently treating not only low-immunogenic TNBC but also other similar tumors, bringing new hope for future clinical treatments.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Qingxia Yuan,Rongyi Liang,Kunling Lv,Xiaohuo Shi,Jing Leng,Yonghong Liu,Jian Xiao,Lifeng Zhang,Longyan Zhao
Chlorella polysaccharides have been gaining increasing attention because of their high yield from dried Chlorella powder and their remarkable immunomodulatory activity. In this study, the major polysaccharide fraction, CPP-3a, in Chlorella pyrenoidosa , was isolated, and its detailed structure was investigated by analyzing the low-molecular-weight product prepared via free radical depolymerization. The results indicated that CPP-3a with a molecular weight of 195.2 kDa was formed by →2)-α-L-Ara f -(1→, →2)-α-D-Rha p -(1→, →5)-α-L-Ara f -(1→, →3)-β-D-Glc p- (1→, →4)-α-D-Glc p- (1→, →4)-α-D-Glc p A-(1→, →2,3)-α-D-Man p- (1→, →3,4)-α-D-Man p- (1→, →3,4)-β-D-Gal p- (1→, →3,6)-β-D-Gal p- (1→, and →2,3,6)-α-D-Gal p- (1→ residues, branched at C2, C3, C4, or C6 of α/β-D-Gal p and α-D-Man p , and terminated by α/β-L-Ara f , α-L-Ara p , α-D-Gal p , and β-D-Glc p . Biological assays showed that CPP-3a significantly altered the dendritic morphology of immature dendritic cells (DCs). Enhanced CD80, CD86, and MHC I expression on the cell surface and decreased phagocytic ability indicated that CPP-3a could induce the maturation of DCs. Furthermore, CPP-3a-stimulated DCs not only stimulated the proliferation of allogeneic naïve CD4 + T cells and the secretion of IFN-γ, but also directly stimulated the activation and proliferation of CD8 + T cells through cross-antigen presentation. These findings indicate that CPP-3a can promote human DC maturation and T-cell stimulation and may be a novel DC maturation inducer with potential developmental value in DC immunotherapy.
研究领域:
免疫学
·
生物化学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2019
·Vol. 7
·期 31
·4854-4866
·
IF 5.047
Xuanjin Wu,Yang Li,Xiguang Chen,Zhongzheng Zhou,Jianhui Pang,Xin Luo,Ming Kong
The efficient delivery of vaccines to draining lymph nodes and the induction of robust local immune responses are crucial for immunotherapy. Transdermal administration has been evidenced to facilitate the delivery of ingredients to lymph nodes. In this study, transfersomes with opposite surface charges were applied for antigen encapsulation and these were integrated with dissolving microneedles to investigate their effects on immune responses via transdermal immunization. The microneedles were easily inserted into mouse skin and achieved the local release of nanovaccines into the dermis through dissolution. Although anionic nanovaccines promoted cellular uptake via DC2.4, cationic nanovaccines exhibited stronger escape capacities from endocytic compartments, facilitating antigen processing via an MHC-I presentation pathway, and formed larger accumulations in lymph nodes. Compared with their anionic counterparts, the cationic nanovaccines more efficiently activated DC maturation and induced Th1 immunity; this was suggested by the significantly increased IgG2a/IgG1 ratio and elevated cytokine secretion from Th1 cells, without an enhancement in the Th2 response. Such an enhanced Th1 antigen-specific immune response in lymph nodes via a transdermal vaccine delivery platform is beneficial for potential immunotherapy approaches.
研究领域:
免疫学
·
药学
·
纳米技术
·
疫苗递送系统
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2018
·
IF 8.097
Dandan Jiang,Weiwei Mu,Xiuping Pang,Yongjun Liu,Na Zhang,Yunmei Song,Sanjay Garg
Enhancing cytosol delivery of exogenous antigens in antigen presenting cells can improve cross-presentation and CD8+ T cell-mediated immune response. The antigen cytosol delivery speed, which has great importance on the rate of MHC class I molecules (MHC I) antigen presentation pathway and cytotoxic T lymphocytes (CTLs) induction, has not been well studied. We hypothesized that micelle-tailored vaccine with multiple cascaded lysosomal responsive capabilities could accelerate lysosomal escape and enhance cancer immunotherapy. To test our hypothesis, we created a novel micellar cancer vaccine (ovalbumin-loaded pH/redox dual-sensitive micellar vaccine, OLM-D) by cleavable conjugation of an antigen with house-made amphiphilic poly(l-histidine)–poly(ethylene glycol) (PLH–PEG) in current study. OLM-D was supposed to achieve cascade cytosol delivery of ovalbumin through three steps in terms of (i) initial redox triggered ovalbumin release, (ii) promoted proton inflow and micelle disassembly, and (iii) speeded proton sponge effect and lysosome bulging/broke. Redox-sensitive antigen release and consequently accelerative OLM-D disassembly were confirmed by sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS–PAGE), transmission electronic microscopy (TEM), particle sizes, zeta potentials, and in vitro Ova release evaluation. The speeded cytosol delivery of ovalbumin was visualized under a confocal laser scanning microscope (CLSM). The ability of OLM-D to increase the MHC I molecule combination rate and antigen cross-presentation efficiency was identified by antigen presentation assay and maturation assay in bone marrow-derived dendritic cells (BMDCs). In vivo, the capability of OLM-D to accumulate in draining lymph nodes (LNs) after injection was visualized by real-time near infrared fluorescence imaging (NIRF) and the distribution order in different LNs was first observed (a, d, c, b). Enhanced cancer immunity of OLM-D was confirmed by increased CD3+CD8+ T cell quantity, CD3+CD8+25D11.6+ T cells quantity, and IFN-γ, IL-2 secretion post subcutaneous or intraperitoneal injection (p < 0.05). Taken together, our results indicated that OLM-D provided a promising cascade cytosol delivery strategy, which held great potential to guide further design of nano-particulate cancer vaccines for efficient cancer immunotherapy.
研究领域:
癌症免疫学
·
药学
·
纳米技术
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Lei Cao,Dongsheng Tang,Zhen Yu,Yue Shen,Yang Wang,Yue-Qin Li,Juan Chen,Zhao-Qian Liu,Ji-Ye Yin,Haihua Xiao,Xiang-Ping Li
Endogenous T cell activation relies on recognizing tumor-specific antigens. However, tumor cells often alter phenotypes to evade immune surveillance, resulting in immune escape and drug resistance. Photodynamic therapy (PDT) activates anti-tumor immune responses by generating reactive oxygen species, which induce endoplasmic reticulum stress and immunogenic cell death. The clinical application of PDT is limited by immunosuppressive tumor microenvironment. Notably, enhancer of zeste homolog 2 (EZH2) regulates expression of immune-related genes in tumor and immune cells through H3K27 methylation. Consequently, targeting EZH2-mediated epigenetic silence provides an effective strategy to enhance the anti-tumor immune effect of PDT. In this study, a nano-delivery system (NP2) is designed to demonstrate PDT and epigenetic reprogramming effects. NP2 can reverse epigenetic silence, enhance MHC-I expression, and induce release of CXCL9-10 via EZH2i. Meanwhile, NP2 has a significant effect on PDT, inducing endoplasmic reticulum stress that resulted in immunogenic cell death and subsequent activation of the immune cascade. In a mouse model of in situ breast cancer, the combination of PDT activation and epigenetic reprogramming through EZH2i showed synergistic effects on remolding, and triggering a robust anti-tumor immune response in vivo. This study provides a novel idea for improving the immunosuppressive environment in clinical individualized immunotherapy.
研究领域:
癌症生物学
·
免疫学
·
纳米技术
·
药理学
✓ 已验证
产品关联
DOI
高影响因子
ORAL DISEASES
·
2024
·
IF 2.9
Qin Jiang,Fang Wang,Gang Zhou
Objective Oral lichen planus (OLP) is a chronic inflammatory disease characterized by a dense T-cell infiltration and the degeneration of basal keratinocytes. The potential functions of mucosal associated invariant T (MAIT) cells in OLP have been analyzed in our previous study. Keratinocytes under proinflammatory conditions have been demonstrated to activate T cells. This study was aimed to investigate how keratinocytes stimulate MAIT cells in OLP, and to explore the role of activated MAIT cells on keratinocytes. Methods and Results Increased MAIT cells and higher activation marker CD69 were detected in OLP lesions by flow cytometry. The enhanced expression of MHC class I-like molecule (MR1) required for MAIT cell activation in the epithelial layer of OLP lesions was determined by immunohistochemistry. Keratinocytes treated by 5-A-RU prodrug and lipopolysaccharide, respectively, exhibited higher expression of MR1 and secretion of IL-18. In direct coculture systems consisting of keratinocytes and peripheral blood mononuclear cells, both 5-A-RU prodrug-pretreated keratinocytes and lipopolysaccharide-pretreated keratinocytes activated MAIT cells to secrete granzyme B, contributing to elevated keratinocyte apoptosis. Conclusions Keratinocytes were capable to activate MAIT cells via MR1 and cytokines in OLP, and granzyme B produced by activated MAIT cells intensified keratinocyte apoptosis, engaging in the pathogenesis of OLP.
研究领域:
免疫学
·
皮肤病学
·
口腔病理学
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Yinghao Ding,Xueying Zhu,Jian Wen,Junchao Xiong,Shengyi Zhang,Zhimou Yang,Zhi-Wen Hu
Antigen presentation deficiency restricted by class I major histocompatibility complex (MHC-I) causes low antigenicity and antigen escape in tumors, thereby limiting T-cell immunotherapy outcomes. Here, a combined tumor immunotherapy is developed, in which tumors can present exogenous non-tumor antigens, and adoptively transferred CD8 + T cells specific for these antigens are re-targeted to attack tumors. The approach leverages a cascade-responsive peptide self-assembly to co-deliver suitable antigens and the chemotherapeutic drug camptothecin (CPT) to tumors. As a proof-of-concept, to re-target ovalbumin (OVA)-specific OT-I CD8 + T cells against tumors, PSA (Nap-GFFpYE-ss-Ag) and CPSA (CPT-GFFpYE-ss-Ag) are constructed, containing an OVA-derived epitope OVA 257-264 and/or CPT. The design enables the release of a unique N-terminal extended OVA 257-264 and CPT into the cytosol. As a result, the extended antigen is efficiently presented on the tumor surface by MHC-I, and CPT further enhances this presentation. When combined with adoptively transferred OT-I CD8 + T cells, the approach effectively facilitates CD8 + T cell infiltration and tumor inhibition. Additionally, CPSA treatment sensitizes immune responses to programmed cell death-ligand 1 (PD-L1) blockade, allowing the approach to synergize with an anti-PD-L1 antibody for improved tumor eradication.
研究领域:
肿瘤免疫学
·
纳米医学
·
药物递送系统
·
免疫治疗
·
分子自组装
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Xiaodi Li,Pengfei Yuan,Haiyuan Yang,Xiaoqing Zong,Caiqi Yang,Xinjie Chen,Yuchao Li,Xiaodie Yan,Yaoqi Wen,Tianci Zhu,Qian Zhang,Wei Xue,Jian Dai
One of the major causes of immunotherapy resistance is the loss of major histocompatibility complex class I (MHC-I) molecules in tumor cells or the downregulation of the class I antigen presentation pathway. In this study, a novel virus-like nanotherapeutic (siRNA@HCM) is developed via encapsulating nanosized siRNA nanoparticles in a hybrid membrane comprising a personalized tumor cell membrane and a universal 293T membrane expressing the mutant vesicular stomatitis virus glycoprotein (mVSV-G). Upon intravenous administration, siRNA@HCM accumulates at the tumor site and provides two potent driving forces for antitumor immunity. First, mVSV-G induces the fusion of siRNA@HCM with tumor cell membranes and directly injects siRNAs into the cytoplasm, significantly improving tumor intrinsic MHC-I antigen presentation. Moreover, mVSV-G can promote the maturation of dendritic cells, thereby achieving highly efficient antigen cross-presentation. The results demonstrate that spatiotemporally enhancing tumor intrinsic antigen presentation and cross-presentation via siRNA@HCM can achieve satisfactory antitumor efficacy and excellent biocompatibility. Immune infiltration analysis shows that siRNA@HCM treatment turns cold tumors into hot tumors. In addition, it significantly promotes the therapeutic effect of programmed death-1 inhibitor. In summary, virus-like nanotherapeutics present a promising approach to enhance the antitumor immune response, with distinct advantages for potential personalized therapy and clinical applications.
研究领域:
肿瘤学
·
免疫学
·
纳米技术
·
药学
✓ 已验证
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）