细胞程序性坏死是一种依赖于RIP激酶的细胞死亡，参与许多重要疾病的病理过程。我们已发现RIP3调控死亡受体、Toll样受体以及病原体介导的细胞程序性坏死的关键作用。本项目初期工作发现RIP3功能缺失能够显著抑制体内淋巴瘤的生长，RIP3的缺陷显著降低肿瘤微环境中免疫细胞死亡，并提升肿瘤微环境中免疫细胞的比例。而且，我们发现淋巴瘤细胞中RIP3的缺陷不能抑制肿瘤生长，骨髓移植实验表明RIP3在免疫系统中缺失显著抑制肿瘤生长。这些结果表明免疫细胞程序性坏死而非肿瘤细胞坏死在淋巴瘤中起关键作用。在此基础上，我们将重点鉴定调控肿瘤微环境中免疫细胞程序性坏死的因子及其作用机制，明确发生程序性坏死的特定免疫细胞类群，从机制上揭示肿瘤微环境中免疫细胞程序性坏死的激活机制以及信号转导通路，并从功能上阐明免疫细胞程序性坏死对肿瘤微环境中免疫功能以及淋巴瘤等肿瘤发生发展的调控作用，为肿瘤治疗提供新的思路。

Necroptosis/programmed necrosis is a form of necrosis that depends on RIP kinase and plays an important role in the pathogenesis of many human diseases. We have found that RIP3 is key regulator in the necroptosis induced by the activation of death receptors and Toll like receptors, and pathogen infection. In the initial work of this project, we found that RIP3 dysfunction could significantly inhibit the growth of lymphoma in vivo, and RIP3 deficiency could significantly reduce the death of immune cells in the tumor microenvironment, thereby enhancing the proportion of immune cells in the tumor microenvironment. Moreover, we found that the defect of RIP3 in lymphoma cells could not inhibit tumor growth. Bone marrow transplantation experiment showed that the absence of RIP3 in immune system significantly inhibited tumor growth. These results suggest that necroptosis of immune cells, but not that of tumor cells, plays a key role in the progression of lymphoma. Based on above findings, we will further identify and characterize regulatory factors involved in the necroptotic pathway in immune cells and explore how they regulate necroptosis during tumor development. Moreover, we will investigate the specific immune cells that undergo necroptosis and understand how necroptosis of these immune cells regulates immune responses and tumor development. This study will provide novel opportunities to develop therapeutic strategies for cancer.