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

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

  • J Adv Res. 2024 Aug 17:S2090-1232(24)00363-1. doi: 10.1016/j.jare.2024.08.021.
Shunxi Wang 1,  Xiaoxue Yuan 1,  Zetao Yang 1,  Xuan Zhang 1,  Zhiling Xu 1,  Li Yang 1,  Xian Yang 1,  Wei Zhou 2,  Wanqian Liu 3
Affiliations

Affiliations

  • 1 Key Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China.
  • 2 Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China; Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China. Electronic address: zhouwei998@cqu.edu.cn.
  • 3 Key Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China. Electronic address: wqliu@cqu.edu.cn.
PMID: 39159723 DOI: 10.1016/j.jare.2024.08.021
Abstract

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 promoted xCT-mediated Ferroptosis induced by RSL3 or sorafenib on stiff substrate via FTL, whereas its overexpression abolished these upward trends. Notably, PD-L2 deletion in combination with sorafenib and anti-PD-1 antibody significantly sensitized HCC cells and blunted Cancer growth in vivo. Additionally, we found the ferroptosis- and immune checkpoint-related prognostic genes that combined PD-L2, SLC7A11 and SYMD3 well predict the clinical efficacy of sorafenib in patients with HCC.

Conclusion: These findings expand our understanding of the mechanics-dependent PD-L2 role in Ferroptosis, Cancer progression and resistance, providing a basis for the clinical translation of PD-L2 as a therapeutic target or diagnostic biomarker.

Keywords

Ferroptosis; Hepatocellular carcinoma; Immunotherapy; Matrix stiffness; PD-L2; Sorafenib resistance.

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