靶向上游警报素（TSLP、IL-33、IL-25）：治疗2型慢性鼻窦炎伴鼻息肉的新前沿

文献信息

中文摘要

慢性鼻窦炎伴鼻息肉（CRSwNP）影响全球1%-4%的成人，并对生活质量造成重大负担。尽管采用内镜手术、局部糖皮质激素和全身糖皮质激素治疗，术后5年复发率仍超过54%。即使出现了靶向下游2型效应分子的生物制剂，如度普利尤单抗、美泊利单抗和奥马珠单抗，仍有相当一部分患者，尤其是混合型或非2型内型的患者，未能得到充分控制。上皮警报素——胸腺基质淋巴细胞生成素（TSLP）、白细胞介素-33（IL-33）和白细胞介素-25（IL-25）——位于炎症级联反应的顶端，作为近端触发因子，将先天屏障破坏与适应性2型放大联系起来。本综述探讨了这三种分子在CRSwNP中共同和独特的病理生物学，比较了tezepelumab（3期）、抗IL-33/ST2药物（2/3期）和新兴抗IL-25生物制剂（早期阶段）的临床轨迹，并概述了未来研究的概念框架。我们提出，上游警报素抑制比下游细胞因子阻断提供更广泛的免疫调节范围，但其临床转化取决于三个尚未解决的挑战：克服警报素之间的功能冗余、确定持续上皮-免疫抑制的长期安全性特征，以及验证临床可及的预测性生物标志物。所提出的算法和生物标志物截断值仍属探索性，需要在CRSwNP特异性队列中进行前瞻性验证。

英文摘要

Chronic rhinosinusitis with nasal polyps (CRSwNP) affects 1%-4% of adults globally and imposes a substantial burden on quality of life. Despite endoscopic surgery, topical corticosteroids, and systemic glucocorticoids, postoperative recurrence exceeds 54% at five years. Even with the advent of biologics targeting downstream type 2 effectors, such as dupilumab, mepolizumab, and omalizumab, a meaningful subset of patients, particularly those with mixed or non-type 2 endotypes, remains inadequately controlled. The epithelial alarmins thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and interleukin-25 (IL-25) occupy the apex of the inflammatory cascade, functioning as proximal triggers that bridge innate barrier disruption to adaptive type 2 amplification. This review examines the shared and distinctive pathobiology of these three molecules in CRSwNP, compares the clinical trajectories of tezepelumab (Phase 3), anti-IL-33/ST2 agents (Phase 2/3), and emerging anti-IL-25 biologics (early-phase), and outlines a conceptual framework for future investigation. We propose that upstream alarmin inhibition offers a broader immunomodulatory scope than downstream cytokine blockade, yet its clinical translation hinges on three unresolved challenges: overcoming functional redundancy among alarmins, defining the long-term safety profile of sustained epithelial-immune suppression, and validating clinically accessible predictive biomarkers. The proposed algorithms and biomarker cut-offs remain exploratory and require prospective validation in CRSwNP-specific cohorts.