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

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.