RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题:MgZnFe-layered double hydroxides as a dual-function platform for enhancing subunit vaccine efficacy in tumor immunotherapy.
MgZnFe-layered double hydroxides as a dual-function platform for enhancing subunit vaccine efficacy in tumor immunotherapy.
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治疗性癌症疫苗在免疫治疗中显示出前景,但面临抗原递送不佳、免疫激活不足和免疫抑制性肿瘤微环境等挑战,限制了肿瘤特异性细胞免疫。在本研究中,我们提出了一种双功能肿瘤疫苗平台MgFeZn-层状双氢氧化物(LMFZ),既作为抗原递送系统又作为免疫佐剂以增强抗肿瘤反应。负载抗原后,纳米级LMFZ颗粒高效转运至淋巴结,促进树突状细胞(DCs)对抗原的捕获。LMFZ的内体逃逸使抗原交叉呈递成为可能并增强DC成熟,促进细胞毒性T淋巴细胞增殖和肿瘤浸润。LMFZ还可中和肿瘤酸性、诱导巨噬细胞M1极化,并通过Zn 2+补充增强NK 细胞活性,从而放大抗肿瘤免疫。在小鼠模型中,经两次瘤周皮下注射后,负载抗原的LMFZ表现出显著抗肿瘤疗效且不良反应极小。这凸显了LMFZ疫苗平台临床转化的潜力,并为解决当前治疗性疫苗免疫疗法的局限性提供了创新策略。
Therapeutic cancer vaccines show promise in immunotherapy but face challenges such as poor antigen delivery, insufficient immune activation, and an immunosuppressive tumor microenvironment, limiting tumor-specific cellular immunity. In this study, we present a dual-function tumor vaccine platform, MgFeZn-Layered double hydroxide (LMFZ), serving as both an antigen delivery system and immune adjuvant to enhance antitumor responses. Loaded with antigens, nanometer-sized LMFZ particles efficiently traffic to lymph nodes, promoting antigen capture by dendritic cells (DCs).
LMFZ endosomal escape enables antigen cross-presentation and enhances DC maturation, boosting cytotoxic T lymphocyte proliferation and tumor infiltration. LMFZ also neutralizes tumor acidity, induces M1 polarization of macrophage, and enhances natural killer cell activity via Zn 2+ supplementation, amplifying antitumor immunity.
Following two peritumoral subcutaneous injections, antigen-loaded LMFZ demonstrated significant antitumor efficacy with minimal adverse effects in a mouse model. This highlights the potential of LMFZ vaccine platform for clinical translation and offers an innovative strategy to address the limitations of current therapeutic vaccine-based immunotherapies.
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