Hussain Zubair, Zhang Yueteng, Qiu Lu, Gou Shanshan, Liu Kangdong
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
NPJ Vaccines. 2025 Feb 7;10(1):27. doi: 10.1038/s41541-025-01084-2.
The pivotal role of type 1 conventional dendritic cells (cDC1s) in the field of dendritic cell (DC)-based tumor immunotherapies has been gaining increasing recognition due to their superior antigen cross-presentation abilities and essential role in modulating immune responses. This review specifically highlights the C-type lectin receptor family 9 member A (Clec9a or DNGR-1), which is exclusively expressed on cDC1s and plays a pivotal role in augmenting antigen cross-presentation and cytotoxic T lymphocyte (CTL) responses while simultaneously mitigating off-target effects. These effects include the enhancement of the cDC1s cross-presentation, reducing autoimmune responses and systemic inflammation, as well as preventing the non-specific activation of other immune cells. Consequently, these actions may contribute to reduced toxicity and enhanced treatment efficacy in immunotherapy. The exceptional ability of Clec9a to cross-present dead cell-associated antigens and enhance both humoral and CTL responses makes it an optimal receptor for DC-based strategies aimed at strengthening antitumor immunity. This review provides a comprehensive overview of the molecular characterization, expression, and signaling mechanisms of Clec9a. Furthermore, it discusses the role of Clec9a in the induction and functional activation of Clec9a cDC1s, with a particular focus on addressing the challenges related to off-target effects and immune tolerance in the development of tumor vaccines. Additionally, this review explores the potential of Clec9a-targeted approaches to enhance the immunogenicity of tumor vaccines and addresses the utilization of Clec9a as a delivery target for specific agonists (such as STING agonists and αGC) to enhance their therapeutic effects. This novel approach leverages Clec9a's capacity to improve the precision and efficacy of these immunomodulatory molecules in tumor treatment. In summary, this review presents compelling evidence positioning Clec9a as a promising target for DC-based tumor immunotherapy, capable of enhancing the efficacy of vaccines and immune responses while minimizing adverse effects.
1型传统树突状细胞（cDC1s）在基于树突状细胞（DC）的肿瘤免疫治疗领域中发挥着关键作用，这一点已得到越来越多的认可，因为它们具有卓越的抗原交叉呈递能力以及在调节免疫反应中发挥着重要作用。本综述特别强调了C型凝集素受体家族9成员A（Clec9a或DNGR-1），它仅在cDC1s上表达，在增强抗原交叉呈递和细胞毒性T淋巴细胞（CTL）反应的同时，还能减轻脱靶效应，发挥着关键作用。这些效应包括增强cDC1s的交叉呈递、减少自身免疫反应和全身炎症，以及防止其他免疫细胞的非特异性激活。因此，这些作用可能有助于降低免疫治疗中的毒性并提高治疗效果。Clec9a能够交叉呈递与死细胞相关的抗原，并增强体液免疫和CTL反应，这使其成为旨在增强抗肿瘤免疫力的基于DC的策略的理想受体。本综述全面概述了Clec9a的分子特征、表达和信号传导机制。此外，它还讨论了Clec9a在Clec9a cDC1s的诱导和功能激活中的作用，特别关注解决肿瘤疫苗开发中与脱靶效应和免疫耐受相关的挑战。此外，本综述探讨了以Clec9a为靶点的方法增强肿瘤疫苗免疫原性的潜力，并讨论了将Clec9a用作特定激动剂（如STING激动剂和αGC）的递送靶点以增强其治疗效果。这种新方法利用了Clec9a在肿瘤治疗中提高这些免疫调节分子的精准度和疗效的能力。总之，本综述提供了令人信服的证据，将Clec9a定位为基于DC的肿瘤免疫治疗的一个有前景的靶点，能够在最小化不良反应的同时提高疫苗效力和免疫反应。
