Xu Li, Kong Yi, Li Kang, Li Jia, Xu Fang, Xu Yan, Liang Shuzhi, Chen Bolin
The Second Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan Province, P.R. China.
Clin Transl Med. 2025 Feb;15(2):e70192. doi: 10.1002/ctm2.70192.
To investigate the potential mechanisms underlying neutrophil extracellular traps (NETs) confer ferroptosis resistance and CD8(+) T cell inhibition in lung adenocarcinoma (LUAD). By the intravenous injection of LLC cells into the tail vein, a LUAD mouse model was created. Phorbol-12-myristate-13-acetate (PMA) stimulated neutrophils to facilitate NETs formation and combined with NETs inhibitor DNase I to explore NETs mechanism on LLC cell proliferation, migration, ferroptosis resistance, and CD8(+) T cell activity. CitH3, myeloperoxidase (MPO), cell-free DNA, and MPO-DNA levels in LUAD were increased, indicating an increase in NETs formation in LUAD. PMA promoted NETs formation in tumours of mice, increased the number of CD3(+)CD4(+) T cells, decreased perforin, granzyme A, granzyme B, IFNγ, and TNF-α levels, and promoted LUAD growth and the number of lung tumour nodules, indicating that PMA promoted NETs formation, reduced the activity of CD8(+)T cells, and promoted LUAD growth. DNase I partially reversed the effects of PMA. NETs promoted LLC cell proliferation and migration, while DNase I reversed NETs effects. Erastin inhibited LLC cell proliferation and migration and promoted ferroptosis. NETs partially reversed Erastin effects. Further results showed that NETs promoted LLC cell proliferation and migration and inhibited ferroptosis by promoting YTHDF2-mediated SLC2A3 mRNA degradation. Sh-YTHDF2 partially reversed the effect of NETs on LLC cells, whereas si-SLC2A3 partially reversed sh-YTHDF2 effects on LLC cells. In addition, NETs inhibited LLC cell ferroptosis by inhibiting CD8(+) T cell activity. Sh-YTHDF2 and DNase I inhibited NETs formation in tumours, increased the activity of CD8(+) T cells and inhibited LUAD growth. Our results suggested that NETs promoted the growth of LUAD through inhibiting ferroptosis and CD8(+) T cell activity by promoting YTHDF2-mediated SLC2A3 mRNA degradation.
为了探究中性粒细胞胞外陷阱（NETs）赋予肺腺癌（LUAD）铁死亡抗性和抑制CD8(+) T细胞的潜在机制。通过将LLC细胞尾静脉注射，建立了LUAD小鼠模型。佛波酯-12-肉豆蔻酸酯-13-乙酸酯（PMA）刺激中性粒细胞以促进NETs形成，并与NETs抑制剂脱氧核糖核酸酶I联合使用，以探讨NETs对LLC细胞增殖、迁移、铁死亡抗性和CD8(+) T细胞活性的作用机制。LUAD中瓜氨酸化组蛋白H3（CitH3）、髓过氧化物酶（MPO）、游离DNA和MPO-DNA水平升高，表明LUAD中NETs形成增加。PMA促进小鼠肿瘤中NETs形成，增加CD3(+)CD4(+) T细胞数量，降低穿孔素、颗粒酶A、颗粒酶B、干扰素γ（IFNγ）和肿瘤坏死因子-α（TNF-α）水平，并促进LUAD生长和肺肿瘤结节数量增加，表明PMA促进NETs形成，降低CD8(+) T细胞活性，并促进LUAD生长。脱氧核糖核酸酶I部分逆转了PMA的作用。NETs促进LLC细胞增殖和迁移，而脱氧核糖核酸酶I逆转了NETs的作用。艾拉司丁抑制LLC细胞增殖和迁移并促进铁死亡。NETs部分逆转了艾拉司丁的作用。进一步结果表明，NETs通过促进YTHDF2介导的SLC2A3 mRNA降解促进LLC细胞增殖和迁移并抑制铁死亡。短发夹RNA干扰YTHDF2（Sh-YTHDF2）部分逆转了NETs对LLC细胞的作用，而小干扰RNA干扰SLC2A3（si-SLC2A3）部分逆转了Sh-YTHDF2对LLC细胞的作用。此外，NETs通过抑制CD8(+) T细胞活性抑制LLC细胞铁死亡。Sh-YTHDF2和脱氧核糖核酸酶I抑制肿瘤中NETs形成，增加CD8(+) T细胞活性并抑制LUAD生长。我们的结果表明，NETs通过促进YTHDF2介导的SLC2A3 mRNA降解抑制铁死亡和CD8(+) T细胞活性，从而促进LUAD生长。
