Zhang Jiwei, Wise Steven G, Zuo Shunqing, Bao Shisan, Zhang Xufeng
Department of Thoracic Surgery, Songjiang Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NS, Australia.
Front Immunol. 2025 Mar 21;16:1564357. doi: 10.3389/fimmu.2025.1564357. eCollection 2025.
Lung cancer, a significant global health challenge, is primarily classified into non-small cell lung cancer (NSCLC) and small cell lung cancer. Despite advancements in targeted therapies and immunotherapies, NSCLC outcomes remain poor, with low five-year survival rates. Given the lung's constant exposure to the environment and the presence of mucosal-associated lymphoid tissues, immunity plays a crucial role in NSCLC development. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have shown promise. However, adverse immune events limit their efficacy. This review highlights the contrasting roles of IL-37 and IL-38 in NSCLC pathogenesis. IL-37, an anti-inflammatory cytokine, suppresses tumour growth. It achieves this by modulating macrophage polarization and dendritic cell maturation. Correlations between intra-tumoral IL-37 expression and improved survival suggest a protective role in NSCLC. This may be mediated through VEGF inhibition and immune regulation. Conversely, IL-38, while anti-inflammatory in certain contexts, exhibits a pro-tumorigenic role in NSCLC. IL-38 enhances tumour progression by increasing pro-inflammatory cytokine secretion and facilitating immune evasion, potentially through NF-κB signalling. Notably, IL-38 negatively regulates IL-37, further promoting tumorigenesis. Emerging data suggest that IL-37 has therapeutic potential in inhibiting NSCLC metastasis and supporting immune modulation. In contrast, IL-38 presents a potential target for mitigating pro-inflammatory microenvironment effects. The distinct roles of these cytokines emphasize the complex immune dynamics in NSCLC. Further exploration of their molecular mechanisms and therapeutic implications is warranted. Targeting IL-37 and IL-38 may offer novel strategies for enhancing NSCLC treatment outcomes.
肺癌是一项重大的全球健康挑战，主要分为非小细胞肺癌（NSCLC）和小细胞肺癌。尽管靶向治疗和免疫治疗取得了进展，但NSCLC的治疗效果仍然很差，五年生存率很低。鉴于肺部持续暴露于环境中以及存在黏膜相关淋巴组织，免疫在NSCLC的发展中起着至关重要的作用。靶向PD-1/PD-L1的免疫检查点抑制剂（ICI）已显示出前景。然而，不良免疫事件限制了它们的疗效。本综述强调了IL-37和IL-38在NSCLC发病机制中的相反作用。IL-37是一种抗炎细胞因子，可抑制肿瘤生长。它通过调节巨噬细胞极化和树突状细胞成熟来实现这一点。肿瘤内IL-37表达与生存率提高之间的相关性表明其在NSCLC中具有保护作用。这可能是通过抑制血管内皮生长因子（VEGF）和免疫调节介导的。相反，IL-38虽然在某些情况下具有抗炎作用，但在NSCLC中表现出促肿瘤作用。IL-38通过增加促炎细胞因子分泌和促进免疫逃逸来增强肿瘤进展，可能是通过核因子κB（NF-κB）信号传导。值得注意的是，IL-38负向调节IL-37，进一步促进肿瘤发生。新出现的数据表明，IL-37在抑制NSCLC转移和支持免疫调节方面具有治疗潜力。相比之下，IL-38是减轻促炎微环境影响的潜在靶点。这些细胞因子的不同作用强调了NSCLC中复杂的免疫动态。有必要进一步探索它们的分子机制和治疗意义。靶向IL-37和IL-38可能为提高NSCLC治疗效果提供新的策略。
