PRMT5-mediated methylation of LKB1 controls PD-L1 expression in NSCLC

  • Biomed J. 2026 Jun 10:101002. doi: 10.1016/j.bj.2026.101002.
Yi-Cheng Shen  1 ,  Khuong T L Nguyen  2 ,  Bo-Wei Wang  3 ,  Fang-Ju Cheng  4 ,  Bo-Rong Chen  5 ,  Shu-Wei Hu  3 ,  Po-Yu Chen  6 ,  Jung-Mao Hsu  7 ,  Ya-Ling Wei  3 ,  Wei-Chien Huang  8 ,  Chih-Yen Tu  9 ,  Chia-Hung Chen  10
Affiliations
  • 1. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan; Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, China Medical University Hospital, Taichung, Taiwan.
  • 2. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan; CIRTECH Institute, HUTECH University, Ho Chi Minh City, Vietnam.
  • 3. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
  • 4. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan; Division of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Kyoto University, Kyoto, Japan.
  • 5. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan; Division of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Kyoto University, Kyoto, Japan.
  • 6. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
  • 7. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan.
  • 8. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan; School of Pharmacy, China Medical University, Taichung, Taiwan; Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan; Department of Medical Research, China Medical University Hsinchu Hospital, Hsinchu, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan. Electronic address: [email protected].
  • 9. School of Medicine, China Medical University, Taichung, Taiwan; Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, China Medical University Hospital, Taichung, Taiwan. Electronic address: [email protected].
  • 10. School of Medicine, China Medical University, Taichung, Taiwan; Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, China Medical University Hospital, Taichung, Taiwan. Electronic address: [email protected].
PMID: 42270077 DOI: 10.1016/j.bj.2026.101002
Abstract

Background: Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has significantly improved outcomes in non-small cell lung Cancer (NSCLC), yet resistance remains a major clinical challenge. Protein arginine methyltransferase 5 (PRMT5) is an oncogenic regulator associated with poor prognosis, but its role in immune checkpoint modulation and underlying molecular mechanisms remain incompletely defined.

Materials and methods: PRMT family expression and clinical correlations were analyzed using Oncomine, TCGA, and CPTAC databases. The effect of PRMT5 on PD-L1 was examined in LKB1-proficient and LKB1-deficient NSCLC cell lines using pharmacological inhibitors (GSK3326595, JNJ-64619178) and shRNA knockdown. Mechanistic analyses included co-immunoprecipitation (Co-IP), cycloheximide chase assays, and site-directed mutagenesis of LKB1 arginine residues. T-cell activation was evaluated using co-culture models.

Results: Elevated PRMT5 expression in NSCLC was associated with poor survival, reduced CD4+/CD8+ T-cell infiltration, and higher PD-L1 expression in clinical datasets. Functional analyses revealed context-dependent regulation of PD-L1 by PRMT5. PRMT5 inhibition reduced or failed to induce PD-L1 in LKB1-deficient cells but upregulated PD-L1 in LKB1-proficient cells. Mechanistically, PRMT5 interacted with LKB1 and promoted its degradation through symmetric arginine dimethylation at R409. Conversely, PRMT5 inhibition stabilized LKB1, activated AMPK signaling, and induced PD-L1 expression in LKB1-proficient cells. Combination treatment with a PRMT5 Inhibitor and anti-PD-L1 antibody further enhanced T-cell activation in co-culture models.

Conclusion: These findings identify a PRMT5-LKB1-AMPK regulatory axis controlling PD-L1 expression in a cell-context-dependent manner and suggest that LKB1 status may serve as a predictive biomarker for combining PRMT5 inhibitors with ICB in NSCLC. This strategy offers a potential therapeutic avenue to overcome immunotherapy resistance in LKB1-proficient NSCLC.

Keywords
AMPK; Immunotherapy; LKB1; Methylation; NSCLC; PD-L1; PRMT5.
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