编辑:靶向TNF/TNFR信号通路

• ¹浙江大学，中国
• ²哈佛医学院，美国
• ^3.美国俄亥俄州立大学综合癌症中心

过去三十年对TNFRSF的研究已经在信号通路和受体触发的基本机制方面描绘了这个重要的细胞因子受体家族的复杂图景。现在已经很清楚，抗体激活这些受体并不像受体外结构域的多价接合将受体集中在细胞膜上那么简单，因为受体似乎存在强烈影响信号的特定构象和聚类排列，并且配体诱导的受体聚类模式在TNFRSF的不同成员之间可能存在显著差异(3,4)。此外，在缺少配体的情况下，TNFRSF的不同成员可能具有不同的自抑制机制。因此，TNFRSF信号通路的治疗靶向需要针对受体家族的每个成员进行定制，这将需要深入了解每个TNFRSF成员所采用的受体自抑制和激活的各种机制。本研究课题的目的是收集已知数据，讨论TNFRSF中受体治疗靶向的潜在策略，以及关于受体机制的最新发现。以下是本期贡献的简短摘要。Zaitseva等人提供了针对成纤维细胞生长因子(FGF)诱导的14 (Fn14，也称为TWEAK受体)用于肿瘤治疗的全面更新。Fn14是14 kDa的TNFRSF中的一个小成员，其外膜结构域仅由一个富半胱氨酸结构域(CRD)组成。TWEAK-Fn14轴与几个生理过程有关。特别是，它似乎在急性损伤后的组织修复中起着重要的有益作用。 As the authors suggested, the tissue damage that is unavoidably associated with tumor growth triggers tissue repair and thus the tumor microenvironment contains a variety of Fn14-inducing factors and expression of Fn14 has been accordingly reported for a large variety of solid tumors. The signaling pathway of Fn14 is, however, not straightforward. The authors provide an in-depth analysis of how TWEAK/Fn14mediated sequestration of TRAF2-cIAP1/2 complexes can enhance TNF-induced necroptosis as well as enhance nuclear translocation of p52-containing NF-κB in the non-canonical NF-κB pathway. In addition, the authors provide insights into how different formats of the ligand TWEAK, soluble and membrane-anchored, can lead to different signaling outcomes. Overall, this comprehensive review article should be very helpful to those interested in developing new strategies to target the TWEAK-Fn14 axis for tumor therapy.Liu et al contributed an insightful review on antibody-targeted TNFRSF activation for cancer immunotherapy, focusing on the role of Fc-gamma receptor IIB (FcγRIIB) engagement in TNFRSF clustering mediated by agonistic antibodies. TNFR/TNF family interactions provide diversified signals to various types of immune cells at different stages, including inflammation, apoptosis, proliferation and differentiation. Members of the TNFRSF such as CD27, GITR, CD137 and OX40 have been demonstrated to function as T cell co-stimulators. Hence, exploiting the clinical benefit of TNFRSF agonistic antibodies for cancer immunotherapy is of great biomedical interest. The authors reviewed the essential role of FcγRIIB in facilitating multimerization and activation of receptors of the TNFRSF for certain agonistic antibodies, such as DR2, DR5, CD137, OX40, GITR and CD40 agonists. The authors also proposed the working model of xLinkAb for FcγRIIB-dependent TNFRSF clustering bridged by IgGs, which eventually lead to the formation of the multivalent TNFRSFs-IgGs-FcγRIIBs complexes that can activate downstream signaling. Based on the understanding of the structural and functional correlations of agonistic antibodies,