Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC

作者：Shunxi Wang, Xiaoxue Yuan, Zetao Yang, Xuan Zhang, Zhiling Xu, Yang Li, Xian Yang, Wei Zhou, Wanqian Liu · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.08.021 · 被引用次数：25 · 研究领域：Ferroptosis and cancer prognosis、Cancer Immunotherapy and Biomarkers、Immune cells in cancer

INTRODUCTION: Heterogeneous tissue stiffening promotes tumor progression and resistance, and predicts a poor clinical outcome in patients with hepatocellular carcinoma (HCC). Ferroptosis, a congenital tumor suppressive mechanism, mediates the anticancer activity of various tumor suppressors, including immune checkpoint inhibitors, and its induction is currently considered a promising treatment strategy. However, the role of extracellular matrix (ECM) stiffness in regulating ferroptosis and ferroptosis-targeted resistance in HCC remains unclear. OBJECTIVES: This research aimed to explore how extracellular matrix stiffness affects ferroptosis and its treatment efficacy in HCC. METHODS: Ferroptosis analysis was confirmed via cell activity, intracellular ferrous irons, and mitochondrial pathology assays. Baseline PD-L2, SMYD3, and SLC7A11 (xCT) were evaluated in 67 sorafenib-treated patients with HCC (46 for non-responder and 21 for responder) from public data. The combined efficacy of shPD-L2, sorafenib, and anti-PD-1 antibody in HCC was investigated in vivo. RESULTS: Here, we revealed that matrix stiffness-induced PD-L2 functions as a suppressor of xCT-mediated ferroptosis to promote cancer growth and sorafenib resistance in patients with HCC. Mechanically, matrix stiffening induced the expression of PD-L2 by activating SMYD3/H3K4me3, which acts as an RNA binding protein to enhance the mRNA stability of FTL and elevate its protein level. Knockdown of PD-L2 significantly promote...