放化疗对肿瘤微环境TME的改造导致治疗抗性受到日益关注。治疗诱导肿瘤相关巨噬细胞TAM分泌的炎性因子TNFα介导和参与了炎性微环境的形成。研究表明TNFα能够维持Wnt通路的活性，但其激活机制不清。我们前期发现，TNFR超家族成员EBV-LMP1可与Wnt成员Dvl2相互作用，从而激活Wnt通路；TNFR超家族其他成员如TNFR、CD40也与Dvl2相互作用。我们提出：放疗可使肿瘤细胞释放携带LMP1的exosome对肿瘤微环境进行改造：一方面LMP1-exosome激活TAM，释放TNFα，进一步激活肿瘤细胞Wnt通路；另一方面LMP1-exosome通过作用于其他肿瘤细胞，激活Wnt通路，导致肿瘤细胞干性增强，引起放疗抵抗。本项目将以鼻咽癌为模型，通过对TNFR超家族和肿瘤治疗后TME改变的研究，探讨放疗后TAM释放的TNFα对Wnt通路调控的新机制及其在放疗抵抗中的作用与意义。

Therapy-induced changes in tumor microenvironment (TME) are now widely appreciated. Proinflammatory cytokine TNFα released from tumor associated macrophages (TAM) plays a pivotal role in TME modification. It has been reported that TNFα was involved in activation of Wnt pathway; however the underlying mechanism is not clear. We previously demonstrated that EBV-LMP1, a member of TNFR superfamily, can interact with Dvl2 (a component of canonical Wnt pathway) and other members of the superfamily can also do so. Thus, we hypothesize that the TME may be modified by LMP1-containing exosomes, which in one hand activate TAM to release TNFα that activates Wnt signaling in tumors, in other hand, are fused with LMP1-nagative cancer cells, activate Wnt pathway and increase the stemness of the cells, leading to radio-resistance. To experimentally validate our hypothesis, we will investigate radiotherapy-induced changes in TME via TNFR superfamily and establish the detailed mechanisms of the activation of Wnt signaling network by TNF from TAM in nasopharyngeal carcinoma following radiotherapy insult.