LRG1 Drives Pathological Angiogenesis by Disrupting Neutrophil Mitochondrial Homeostasis in Bladder Cancer

ABSTRACT Abnormal tumor vasculature creates a permissive microenvironment that fuels the malignant progression of bladder cancer (BCa). While Leucine‐rich alpha‐2 glycoprotein 1 (LRG1) is known to regulate angiogenesis, its specific role in remodeling the BCa microenvironment remains poorly defined.We integrated single‐cell RNA sequencing (scRNA‐seq) with bulk transcriptomic datasets to identify key cellular subclusters. Functional validation was performed using subcutaneous and orthotopic BCa mouse models, neutrophil depletion, DNase I treatment, and clinical specimens. The molecular interactome was mapped via pull‐down assays, mass spectrometry, and confocal imaging.LRG1 is significantly upregulated in BCa and correlates with hematogenous metastasis and poor prognosis. Mechanistically, tumor‐derived LRG1 binds to Annexin A2 (ANXA2) on neutrophils through its LRR domain, impeding the mitochondrial translocation of Akt and triggering mtROS‐dependent release of Neutrophil Extracellular Traps (NETs). These NETs directly cause vascular destabilization by stripping mural cell coverage. Blockade of the LRG1‐NETosis axis induces vascular normalization, effectively overcoming microenvironmental barriers to increase drug delivery and T‐cell infiltration, thereby profoundly sensitizing BCa to cisplatin and anti‐PD‐1 therapy.The LRG1‐neutrophil‐NETosis axis is a critical driver of vascular dysfunction and therapeutic resistance in BCa. Targeting this axis represents a promising translational strategy to improve clinical outcomes.