The hypoxic ECM and neutrophils in MIBC immunotherapy resistance.

IF 14.6 1区医学 Q1 UROLOGY & NEPHROLOGY

Nature Reviews Urology Pub Date : 2025-10-13 DOI:10.1038/s41585-025-01092-w

Fraser Child,Sapna Lunj,Julie Gough,Martin J Humphries,Luisa Vanesa Biolatti,Peter J Hoskin,Ananya Choudhury,Conrado Guerrero Quiles

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引用次数: 0

Abstract

Immune-checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD1) and programmed cell death 1 ligand 1 (PDL1) have improved survival for patients with different types of solid tumour. However, clinical response in patients with muscle-invasive bladder cancer (MIBC) is limited, with only 20-30% demonstrating a sustained response. An improved understanding of ICI mechanisms and robust biomarkers will increase efficacy and enable patient stratification in MIBC. Hypoxia (low oxygen tension) and neutrophil infiltration are prevalent in MIBC and are associated with immunotherapy resistance. Hypoxia-associated extracellular matrix (ECM) remodelling can induce pro-tumour or anti-tumour neutrophil polarization through biomechanical and biochemical signalling. Hypoxia-associated ECM mechanisms alter neutrophil recruitment, polarization, activation and affect T cell-centric immunotherapies. However, the specific mechanisms by which hypoxia, ECM and neutrophils confer immunotherapy resistance in MIBC are not yet fully understood. ICI resistance could be overcome by targeting specific ECM remodelling-related and neutrophil-related pathways to elicit durable and efficacious responses in 70-80% of patients with MIBC who are currently non-responsive to ICIs.

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缺氧ECM和中性粒细胞在MIBC免疫治疗耐药中的作用。

针对程序性细胞死亡1 （PD1）和程序性细胞死亡1配体1 （PDL1）的免疫检查点抑制剂（ICIs）提高了不同类型实体瘤患者的生存率。然而，肌肉浸润性膀胱癌（MIBC）患者的临床反应是有限的，只有20-30%的患者表现出持续的反应。对ICI机制和强大的生物标志物的更好理解将提高疗效，并使MIBC患者分层。缺氧（低氧压）和中性粒细胞浸润在MIBC中普遍存在，并与免疫治疗耐药性有关。缺氧相关的细胞外基质（ECM）重塑可以通过生物力学和生化信号传导诱导促肿瘤或抗肿瘤中性粒细胞极化。缺氧相关的ECM机制改变中性粒细胞募集、极化、激活和影响T细胞中心免疫治疗。然而，缺氧、ECM和中性粒细胞赋予MIBC免疫治疗耐药的具体机制尚不完全清楚。ICI耐药可以通过靶向特异性ECM重塑相关和中性粒细胞相关途径来克服，从而在目前对ICI无反应的70-80%的MIBC患者中引起持久和有效的应答。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Reviews Urology 医学-泌尿学与肾脏学

CiteScore

12.50

自引率

2.60%

发文量

123

审稿时长

6-12 weeks

期刊介绍： Nature Reviews Urology is part of the Nature Reviews portfolio of journals.Nature Reviews' basic, translational and clinical content is written by internationally renowned basic and clinical academics and researchers. This journal targeted readers in the biological and medical sciences, from the postgraduate level upwards, aiming to be accessible to professionals in any biological or medical discipline. The journal features authoritative In-depth Reviews providing up-to-date information on topics within a field's history and development. Perspectives, News & Views articles, and the Research Highlights section offer topical discussions and opinions, filtering primary research from various medical journals. Covering a wide range of subjects, including andrology, urologic oncology, and imaging, Nature Reviews provides valuable insights for practitioners, researchers, and academics within urology and related fields.