A RIPK3-independent role of MLKL in suppressing parthanatos promotes immune evasion in hepatocellular carcinoma
Xi‐Fei Jiang, Wenjia Deng, Siyao Tao, Zheng Tang, Yuehong Chen, Meng‐Xin Tian, Ting Wang, Chenyang Tao, Yize Li, Yuan Fang, Congying Pu, Jun Gao, Xiaomin Wang, Wei‐Feng Qu, Xiameng Gai, Zhen‐Bin Ding, Yixian Fu, Y. H. Zheng, Siyuwei Cao, Jian Zhou, Min Huang, Weiren Liu, Jun Xu, Jia Fan, Ying–Hong Shi
Abstract
Abstract Mixed lineage kinase domain-like (MLKL) is widely accepted as an executioner of necroptosis, in which MLKL mediates necroptotic signaling and triggers cell death in a receptor-interacting protein kinase 3 (RIPK3)-dependent manner. Recently, it is increasingly noted that RIPK3 is intrinsically silenced in hepatocytes, raising a question about the role of MLKL in hepatocellular carcinoma (HCC). This study reports a previously unrecognized role of MLKL in regulating parthanatos, a programmed cell death distinct from necroptosis. In HCC cells with intrinsic RIPK3 deficiency, knockout of MLKL impedes the orthotopic tumor growth, activates the anti-tumor immune response and enhances the therapeutic effect of immune checkpoint blockade in syngeneic HCC tumor models. Mechanistically, MLKL is required for maintaining the endoplasmic reticulum (ER)-mitochondrial Mg 2+ dynamics in HCC cells. MLKL deficiency restricts ER Mg 2+ release and mitochondrial Mg 2+ uptake, leading to ER dysfunction and mitochondrial oxidative stress, which together confer increased susceptibility to metabolic stress-induced parthanatos. Importantly, pharmacological inhibition of poly(ADP-ribose) polymerase to block parthanatos restores the tumor growth and immune evasion in MLKL-knockout HCC tumors. Together, our data demonstrate a new RIPK3-independent role of MLKL in regulating parthanatos and highlight the role of MLKL in facilitating immune evasion in HCC.