Shi Yueli, Xu Zhiyong, Wang Huan, Tang Bufu, Maihemuti Nueraili, Jiang Xinyuan, Chen Xiuying, Xiao Mingshu, Jiang Sujing, Xu Yun, Xiao Peng, Zhao Jiangnan, Zhang Kaiyue, Li Mengshu, Wang Kai
Department of Respiratory and Critical Care Medicine, Center for Oncology Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China.
Zhejiang Key Laboratory of Precision Diagnosis and Treatment for Lung Cancer, Yiwu, 322000, China.
Adv Sci (Weinh). 2025 Sep;12(34):e16476. doi: 10.1002/advs.202416476. Epub 2025 Jun 19.
Angiogenesis is vital for tumor growth and metastasis, with tumor-associated macrophages (TAMs) being key pro-angiogenic cells recruited by tumor-secreted chemokines. High levels of TAMs contribute to tumor progression and antiangiogenic therapy resistance. Therefore, intensive study of the regulatory mechanisms of TAMs recruitment during tumor development is important for the discovery of new antitumor and antiangiogenic therapeutic strategies. Here, we found that in lung adenocarcinoma (LUAD), ENH levels positively correlated with microvessel density and TAMs infiltration. Further exploration revealed that ENH promoted LUAD angiogenesis and growth by stimulating TAMs recruitment and M2 polarization. Mechanistically, ENH in LUAD induced YAP nuclear aggregation to promote CCL5 transcription, thereby increasing monocyte chemotaxis and ultimately increasing TAMs infiltration and M2 polarization. Besides, we found that ENH interacted with YAP through LIM domains, which significantly triggered the formation of YAP-KPNA2 complexes. Consequently, YAP is imported into the nucleus by KPNA2 and then promoted CCL5 transcription. Notably, ENH knockdown also significantly increased the chemosensitivity. Together, ENH functions in LUAD cells to mediate macrophage infiltration and M2 polarization, which in turn promotes tumor angiogenesis and growth, and targeting ENH offers a promising target for antiangiogenic therapy through immune modulation.
血管生成对肿瘤的生长和转移至关重要，肿瘤相关巨噬细胞（TAM）是肿瘤分泌的趋化因子招募的关键促血管生成细胞。高水平的TAM有助于肿瘤进展和抗血管生成治疗抵抗。因此，深入研究肿瘤发生过程中TAM招募的调控机制对于发现新的抗肿瘤和抗血管生成治疗策略具有重要意义。在此，我们发现，在肺腺癌（LUAD）中，ENH水平与微血管密度和TAM浸润呈正相关。进一步研究发现，ENH通过刺激TAM招募和M2极化促进LUAD血管生成和生长。机制上，LUAD中的ENH诱导YAP核聚集以促进CCL5转录，从而增加单核细胞趋化性并最终增加TAM浸润和M2极化。此外，我们发现ENH通过LIM结构域与YAP相互作用，这显著触发了YAP-KPNA2复合物的形成。因此，YAP被KPNA2导入细胞核，然后促进CCL5转录。值得注意的是，ENH敲低也显著增加了化疗敏感性。总之，ENH在LUAD细胞中发挥作用，介导巨噬细胞浸润和M2极化，进而促进肿瘤血管生成和生长，靶向ENH为通过免疫调节进行抗血管生成治疗提供了一个有前景的靶点。
