Zhou Yixin, Teng Wenjin, Wu Jianchun, Luo Yingbin, Wang Yuli, Li Yan
Clinical Medical Center of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, No.274, Middle Zhijiang Road, Shanghai, 200071, P. R. China.
Biol Proced Online. 2025 May 22;27(1):18. doi: 10.1186/s12575-025-00279-0.
Lung cancer is the leading cause of cancer-related deaths globally. Prolonged targeted therapy use can lead to drug resistance and target mismatches, necessitating more effective and safer treatment strategies. Recent research has focused on the tumor microenvironment, which includes immune and stromal cells that play roles in tumor proliferation, metastasis, and neovascularization. Tumor-associated macrophages (TAMs) are key immune cells in the tumor microenvironment, promoting tumor invasion, metastasis, and immune escape. Their infiltration density in lung cancer tissue is a poor prognostic factor. Piperlongumine (PL), extracted from Piper longum, possesses antitumor and anti-inflammatory properties, inducing apoptosis and inhibiting invasion and metastasis in lung cancer cells. This study aims to elucidate the correlation between endoplasmic reticulum stress (ERS) in lung cancer cells and M2-type TAM polarization and the role of PL in regulating lung cancer progression. The network pharmacologic analysis revealed that Piperlongumine inhibits lung cancer progression by inducing endoplasmic reticulum stress. In vivo experiments demonstrated that Piperlongumine significantly reduced tumor volume and decreased the proportion of M2-type macrophages. Within the co-culture system, lung cancer cells were shown to promote macrophage M2-type polarization and enhance cancer cell migration. Piperlongumine effectively inhibited these effects by inducing endoplasmic reticulum stress in cancer cells, thereby reducing M2 polarization and cell migration. The addition of endoplasmic reticulum stress inhibitor 4-PBA counteracted Piperlongumine's effects, further underscoring the crucial role of ERS in the treatment mechanism. Piperlongumine suppresses lung cancer growth by inducing endoplasmic reticulum stress, which inhibits macrophage M2-type polarization and reduces cell migration. These findings support Piperlongumine's potential as a therapeutic agent and offer a foundation for targeting endoplasmic reticulum stress to modulate TAM function in lung cancer treatment.
肺癌是全球癌症相关死亡的主要原因。长期使用靶向治疗会导致耐药性和靶点不匹配，因此需要更有效、更安全的治疗策略。最近的研究集中在肿瘤微环境上，其中包括在肿瘤增殖、转移和新血管形成中起作用的免疫细胞和基质细胞。肿瘤相关巨噬细胞（TAM）是肿瘤微环境中的关键免疫细胞，促进肿瘤侵袭、转移和免疫逃逸。它们在肺癌组织中的浸润密度是一个不良预后因素。从荜茇中提取的胡椒碱（PL）具有抗肿瘤和抗炎特性，可诱导肺癌细胞凋亡并抑制其侵袭和转移。本研究旨在阐明肺癌细胞内质网应激（ERS）与M2型TAM极化之间的相关性以及PL在调节肺癌进展中的作用。网络药理学分析表明，胡椒碱通过诱导内质网应激抑制肺癌进展。体内实验表明，胡椒碱显著减小肿瘤体积并降低M2型巨噬细胞的比例。在共培养系统中，肺癌细胞可促进巨噬细胞M2型极化并增强癌细胞迁移。胡椒碱通过诱导癌细胞内质网应激有效抑制这些作用，从而减少M2极化和细胞迁移。内质网应激抑制剂4-PBA的加入抵消了胡椒碱的作用，进一步强调了ERS在治疗机制中的关键作用。胡椒碱通过诱导内质网应激抑制肺癌生长，内质网应激抑制巨噬细胞M2型极化并减少细胞迁移。这些发现支持了胡椒碱作为治疗剂的潜力，并为靶向内质网应激以调节肺癌治疗中TAM功能提供了基础。
