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Objective <p>This study aims to investigate the role and molecular mechanism of circRNA circDNER in lung cancer immune evasion by modulating histone lactylation modification through glutamine metabolic reprogramming to regulate PD-L1 expression.</p> Methods <p>Lung cancer cell models (A549, H1975) were constructed by knocking down circDNER using shRNA (shcircDNER group) and overexpressing PD-L1 (PD-L1 group). A murine LLC xenograft model (C57BL/6, <i>n</i> = 8/group) was used for in vivo studies. The expression and interaction of circDNER, H3K18la, and PD-L1 were analyzed using qPCR, ChIP-qPCR, and dual-luciferase reporter assays. Metabolic reprogramming and immune evasion phenotypes were evaluated through metabolite assays (glutamate, α-KG, lactate), colony formation assays, ELISA (IL-2, IFN-γ), and immunohistochemistry (CD8 + T cells, GZMB).</p> Results <p>circDNER was significantly elevated in lung cancer tissues and cell lines. Knockdown of circDNER resulted in a 70% reduction in its expression (<i>P</i> &lt; 0.01) and led to significant decreases in the levels of key metabolites, including glutamate (58%), α-ketoglutarate (53%), and lactate (47%) (all <i>P</i> &lt; 0.01). Functional assays revealed that circDNER silencing enhanced T cell-mediated cytotoxicity, as evidenced by a 63% reduction in cancer cell colony formation (<i>P</i> &lt; 0.01) and increased secretion of IL-2 (1.8-fold) and IFN-γ (1.6-fold) from T cells (both <i>P</i> &lt; 0.01). In vivo, circDNER knockdown suppressed tumor growth, with a 52% reduction in tumor volume and a 45% decrease in tumor weight (both <i>P</i> &lt; 0.01), and promoted anti-tumor immunity, marked by a 2.3-fold increase in CD8 + T cell infiltration and a 1.9-fold expansion of granzyme B-positive areas (both <i>P</i> &lt; 0.01). Mechanistically, circDNER knockdown reduced global histone H3K18 lactylation (H3K18la) levels by 68% (<i>P</i> &lt; 0.01) and diminished H3K18la enrichment at the PD-L1 promoter by 65% (<i>P</i> &lt; 0.01), resulting in a 59% inhibition of PD-L1 promoter activity and a 72% downregulation of PD-L1 protein expression (both <i>P</i> &lt; 0.01). Notably, PD-L1 overexpression reversed the metabolic and immunosuppressive effects of circDNER knockdown, which were subsequently counteracted by concurrent circDNER silencing.</p> Conclusion <p>circDNER enhances glutamine metabolism to promote histone H3K18 lactylation modification, thereby activating PD-L1 transcription and driving lung cancer immune evasion. Targeting the circDNER-H3K18la-PD-L1 axis may provide a novel strategy to overcome immune resistance in lung cancer therapy.</p>

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CircRNA circdner mediates histone lactylation modification via glutamine metabolic reprogramming to regulate PD-L1 expression and promote immune evasion in lung cancer

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  • 发表日期：

    2025年12月29日

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  • Shi-Wei Xu,
  • Tong Liu,
  • Shi-Yin Liu,
  • Ming-Long Li,
  • Wei-Min Zhang,
  • Yuan Weng,
  • Gu-Ye Lu,
  • Hai-Feng Wang,
  • Jin-You Li

摘要

Objective

This study aims to investigate the role and molecular mechanism of circRNA circDNER in lung cancer immune evasion by modulating histone lactylation modification through glutamine metabolic reprogramming to regulate PD-L1 expression.

Methods

Lung cancer cell models (A549, H1975) were constructed by knocking down circDNER using shRNA (shcircDNER group) and overexpressing PD-L1 (PD-L1 group). A murine LLC xenograft model (C57BL/6, n = 8/group) was used for in vivo studies. The expression and interaction of circDNER, H3K18la, and PD-L1 were analyzed using qPCR, ChIP-qPCR, and dual-luciferase reporter assays. Metabolic reprogramming and immune evasion phenotypes were evaluated through metabolite assays (glutamate, α-KG, lactate), colony formation assays, ELISA (IL-2, IFN-γ), and immunohistochemistry (CD8 + T cells, GZMB).

Results

circDNER was significantly elevated in lung cancer tissues and cell lines. Knockdown of circDNER resulted in a 70% reduction in its expression (P < 0.01) and led to significant decreases in the levels of key metabolites, including glutamate (58%), α-ketoglutarate (53%), and lactate (47%) (all P < 0.01). Functional assays revealed that circDNER silencing enhanced T cell-mediated cytotoxicity, as evidenced by a 63% reduction in cancer cell colony formation (P < 0.01) and increased secretion of IL-2 (1.8-fold) and IFN-γ (1.6-fold) from T cells (both P < 0.01). In vivo, circDNER knockdown suppressed tumor growth, with a 52% reduction in tumor volume and a 45% decrease in tumor weight (both P < 0.01), and promoted anti-tumor immunity, marked by a 2.3-fold increase in CD8 + T cell infiltration and a 1.9-fold expansion of granzyme B-positive areas (both P < 0.01). Mechanistically, circDNER knockdown reduced global histone H3K18 lactylation (H3K18la) levels by 68% (P < 0.01) and diminished H3K18la enrichment at the PD-L1 promoter by 65% (P < 0.01), resulting in a 59% inhibition of PD-L1 promoter activity and a 72% downregulation of PD-L1 protein expression (both P < 0.01). Notably, PD-L1 overexpression reversed the metabolic and immunosuppressive effects of circDNER knockdown, which were subsequently counteracted by concurrent circDNER silencing.

Conclusion

circDNER enhances glutamine metabolism to promote histone H3K18 lactylation modification, thereby activating PD-L1 transcription and driving lung cancer immune evasion. Targeting the circDNER-H3K18la-PD-L1 axis may provide a novel strategy to overcome immune resistance in lung cancer therapy.