Nature Communications
·
2025
·
IF 15.7
Ge Xiaolu,Yu Liang,Zhang Lei,Jia Liqing,Meng Mingjing,He Jingquan,Bu Fan,Song Yue,Sun Gaorui,Lv Shiming,Mei Desheng,Yang Yutao,Xu Dakang,Zhang Jingfa,Zhang Shengping,Wang Chuangui,Jia Deshui,Chen Yongping,Gao Yue,He Baokun
The lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency causes severe autoimmune diseases and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) loss in humans. However, the impact of LRBA on antitumor immunity remains understudied. Here we show the important role of LRBA in antitumor immunity and develop small molecules targeting LRBA for cancer immunotherapy. Interestingly, LRBA is negatively associated with antitumor immunity in human patients and mouse models. Using high-throughput screening and subsequent hit optimization, we discover a small molecule LC427 that facilitates the lysosomal degradation of CTLA4 and bolsters survival of activated T cells by binding directly to LRBA and inhibiting the LRBA-CTLA4 interaction. Orally administrated LC427 increases tumor-infiltrating CD8 + T cells and displays effective antitumor activity in multiple mouse tumor models. Notably, LC427 does not induce immune-related adverse events observed with immune checkpoint inhibitors in colitis models. Our study demonstrates that targeting LRBA offers an effective strategy for cancer immunotherapy.
研究领域:
免疫学
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肿瘤学
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药理学
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药物发现
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Wenjin Zhong,Pengcheng Wang,Jintian Wang,Yuejia Zhu,Liquan Chen,Yilong Qian,Xiang Huang,Kai Ye
Background The immune checkpoint inhibitor (ICI) PD-1α can effectively treat Lynch syndrome (LS)-associated colorectal cancer (CRC) (LS-CRC). In some cases, LS-CRC is not sensitive to ICIs. Dendritic cell (DC)-based hybrid membrane nanoparticles have great potential to upgrade the efficacy of ICIs, which can theoretically be applied to enhance the efficacy of ICIs in treating LS-CRC. Methods MnO 2 nanomaterials with si-CTLA4 were absorbed by coating mature DCs loaded with PD-1α and liposome hybrid membranes. The morphology and physicochemical properties of DCsLipo@MnO 2 @si-CTLA4@PD-1α were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering (DLS), fluorescence resonance energy transfer (FRET), and Fourier transform infrared spectroscopy (FTIR). The activation of DCs and T cells was assessed by utilizing the detection of cell surface markers by flow cytometry. The mRNA levels of CTLA4 in T cells were measured using the qPCR method. The biosafety of DCsLipo@MnO 2 @si-CTLA4@PD-1α was proved by hemolysis test in vitro , CCK-8 assay, and live/dead cell staining. In vitro T-cell uptake experiments proved that the nanomedicine can be effectively absorbed by T cells. Cell proliferation, apoptosis, and ELISA experiments demonstrated that nanomedicine facilitated T-cell proliferation, cytokine secretion, and cancer cytotoxicity. Finally, the anti-cancer effect and immune activation ability of the nanomedicine against LS-CRC were verified by a mouse allograft model. Results The nanomedicine DCsLipo@MnO 2 @si-CTLA4@PD-1α created in this research exhibited good stability and uniform vesicle morphology. In vitro hemolysis test, CCK-8 assay, and live/dead staining experiments indicated that DCsLipo@MnO 2 @si-CTLA4@PD-1α had great biosafety. The nanoparticle loaded with si-CTLA4 effectively reduced the mRNA expression of CTLA4 in T cells. Meanwhile, the results of T cell flow analysis, cell proliferation, cytotoxicity, apoptosis, and ELISA experiments manifested that DCsLipo@MnO 2 @si-CTLA4@PD-1α effectively reinforced the proliferation and activation of T cells, and enhanced the cytotoxicity of T cells to cancer cells. The validation experiments based on the mouse allograft tumor model manifested that DCsLipo@MnO 2 @si-CTLA4@PD-1α boosted the infiltration of T cells into tumor tissues and suppressed the development of LS-CRC. Conclusion DCsLipo@MnO 2 @si-CTLA4@PD-1α can facilitate T cell activation and synergistically enhance the efficacy of ICIs, exhibiting a great inhibitory effect on LS-CRC.
研究领域:
肿瘤学
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免疫学
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生物医学工程
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2019
·Vol. 11
·期 42
·19912-19922
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IF 6.97
Dongsheng Zhang,Ping Cui,Zhichao Dai,Baochan Yang,Xiuxiu Yao,Qingyun Liu,Zunfu Hu,Xiuwen Zheng
The metastasis and recurrence of tumors are the main reasons for cancer death. In this work, a promising therapy for tumor treatment that can eliminate primary tumors and prevent tumor relapses is introduced by combining chemotherapy, photothermal therapy (PTT) and immunotherapy. Multifunctional FePt/MoS2-FA nanocomposites (FPMF NCs) were obtained via anchoring FePt nanoparticles and folic acid (FA) on MoS2 nanosheets. As an efficient ferroptosis agent, FePt nanoparticles could catalyze the Fenton reaction to produce the reactive oxygen species (ROS). Through the highly effective photothermal conversion of MoS2 nanosheets, the primary tumor cells could be ablated by photothermal therapy (PTT). Moreover, the metastatic tumors were eliminated effectively with the help of oligodeoxynucleotides containing cytosine–guanine (CpG ODNs) combined with systemic checkpoint blockade therapy using an anti-CTLA4 antibody. Even more intriguingly, a strong immunological memory effect was obtained by this synergistic therapy. Taking all these results into consideration, we anticipate that the photo-chemo-immunotherapy strategies show great promise toward the development of a multifunctional platform for anticancer therapeutic applications.
研究领域:
肿瘤学
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纳米技术
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免疫疗法
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材料科学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2023
·
IF 13.3
Huilin Zhang,Yiwei Zhang,Haili Hu,Wenqin Yang,Xue Xia,Lei Lei,Ruyi Lin,Jiamei Li,Yuan Li,Huile Gao
Tumor vaccine is a promising cancer treatment modality, however, the convenient antigens loading in vivo and efficient delivery of vaccines to lymph nodes (LNs) still remain a formidable challenge. Herein, an in situ nanovaccine strategy targeting LNs to induce powerful antitumor immune responses by converting the primary tumor into whole-cell antigens and then delivering these antigens and nanoadjuvants simultaneously to LNs is proposed. The in situ nanovaccine is based on a hydrogel system, which loaded with doxorubicin (DOX) and nanoadjuvant CpG-P-ss-M. The gel system exhibits ROS-responsive release of DOX and CpG-P-ss-M, generating abundant in situ storage of whole-cell tumor antigens. CpG-P-ss-M adsorbs tumor antigens through the positive surface charge and achieves charge reversal, forming small-sized and negatively charged tumor vaccines in situ, which are then primed to LNs. Eventually, the tumor vaccine promotes antigens uptake by dendritic cells (DCs), maturation of DCs, and proliferation of T cells. Moreover, the vaccine combined with anti-CTLA4 antibody and losartan inhibits tumor growth by 50%, significantly increasing the percentage of splenic cytotoxic T cells (CTLs), and generating tumor-specific immune responses. Overall, the treatment effectively inhibits primary tumor growth and induces tumor-specific immune response. This study provides a scalable strategy for in situ tumor vaccination.
研究领域:
肿瘤学
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免疫疗法
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纳米技术
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2022
·
IF 10.761
Mengna Wang,Siyu Deng,Yijia Cao,Hang Zhou,Wei Wei,Kexiao Yu,Youde Cao,Bing Liang
The ongoing circulating energy loss, low reactive oxygen species (ROS) accumulation and poor immunogenicity of tumors make it difficult to induce sufficient immunogenic cell death (ICD) in the tumor immunosuppressive microenvironment (TIME), resulting in unsatisfactory immunotherapy efficacy. Furthermore, for highly malignant tumors, simply enhancing ICD is insufficient for exhaustively eliminating the tumor and inhibiting metastasis. Herein, we propose a unique magnetothermal-dynamic immunotherapy strategy based on liquid-solid transformation porous versatile implants (Fe 3 O 4 / [email protected] ) that takes advantage of less energy loss and avoids ongoing circulating losses by minimally invasive injection into tumors. In addition, the magnetothermal effect regresses and eliminates tumors that are not limited by penetration to simultaneously trigger 2,2′-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH) decomposition and generate a large amount of oxygen-irrelevant free radicals and heat shock protein (HSP) accumulation by heating, evoking both intracellular oxidative stress and endoplasmic reticulum (ER) stress to induce large-scale ICD and enhance tumor immunogenicity. More importantly, in orthotopic bilateral breast tumor models, a significant therapeutic effect was obtained after combining amplified ICD with CTLA4 checkpoint blockade. The 21-day primary and distant tumor inhibition rates reached 90%, and the underlying mechanism of the effective synergetic strategy of inducing the T-cell-related response, the immune memory effect and TIME reprogramming in vivo was verified by immune cell analyses. This remarkable therapeutic effect provides a new direction for antitumor immunotherapy based on magnetothermally controlled oxygen-independent free radical release.
研究领域:
肿瘤学
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免疫治疗
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纳米技术
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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