表型可塑性是一个不断上升的癌症标志，LKB1 失活引发的肺腺癌向鳞状细胞转变 (AST) 与耐药性显着相关。迫切需要对 AST 的机制进行深入了解，以确定 LKB1 缺陷型肺癌的治疗脆弱性。在这里，我们发现 KrasLSL-G12D/ 中 AST 期间 10-11 易位 (TET) 介导的 DNA 去甲基化升高； Lkb1L/L (KL) 小鼠，单个 Tet 基因的敲除表明 Tet2 是鳞状细胞转变所必需的。 TET2 通过 STAT3 介导的 CXCL5 表达促进中性粒细胞浸润。靶向 STAT3-CXCL5 连接可通过减少中性粒细胞浸润来有效抑制鳞状细胞转变。有趣的是，肿瘤浸润的中性粒细胞富含甘油三酯，可以将脂质转移到肿瘤细胞，促进细胞增殖和鳞状细胞转变。巨胞饮作用的药理抑制可显着抑制中性粒细胞至癌细胞的脂质转移并阻止鳞状细胞转变。这些数据揭示了通过调节免疫微环境和代谢通讯来协调表型可塑性的表观遗传机制，并确定了抑制 AST 的治疗策略。© 2024 Xu 等人。

Phenotypic plasticity is a rising cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung cancer. Here, we find that ten-eleven translocation (TET)-mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that Tet2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3-CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to-cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.© 2024 Xue et al.