LCK‐Mediated RIPK3 Activation Controls Double‐Positive Thymocyte Proliferation and Restrains Thymic Lymphoma by Regulating the PP2A‐ERK Axis

Abstract Receptor‐interacting protein kinase 3 (RIPK3) is the primary regulator of necroptotic cell death. RIPK3 expression is often silenced in various cancer cells, which suggests that it may have tumor suppressor properties. However, the exact mechanism by which RIPK3 negatively regulates cancer development and progression remains unclear. This report indicates that RIPK3 acts as a potent regulator of the homeostatic proliferation of CD4⁺CD8⁺ double‐positive (DP) thymocytes. Abnormal proliferation of RIPK3‐deficient DP thymocytes occurs independently of the well‐known role for RIPK3 in necroptosis (upstream of MLKL activation), and is associated with an incidental thymic mass, likely thymic hyperplasia. In addition, Ripk3‐null mice develop increased thymic tumor formation accompanied by reduced host survival in the context of an N‐ethyl‐N‐nitrosourea (ENU)‐induced tumor model. Moreover, RIPK3 deficiency in p53‐null mice promotes thymic lymphoma development via upregulated extracellular signal‐regulated kinase (ERK) signaling, which correlates with markedly reduced survival rates. Mechanistically, lymphocyte‐specific protein tyrosine kinase (LCK) activates RIPK3, which in turn leads to increases in the phosphatase activity of protein phosphatase 2 (PP2A), thereby suppressing hyper‐activation of ERK in DP thymocytes. Overall, these findings suggest that a RIPK3‐PP2A‐ERK signaling axis regulates DP thymocyte homeostasis and may provide a potential therapeutic target to improve thymic lymphoma therapies.