Single‐Cell RNA Sequencing Identifies MMP11 ⁺ Cancer‐Associated Fibroblasts as Drivers of Angiogenesis and Bladder Cancer Progression

Abstract Cancer‐associated fibroblasts (CAFs) play a crucial role in tumor progression, with heterogeneity influencing therapeutic response and prognosis, highlighting their potential as viable targets for treatment. In this study, a novel CAF subgroup, MMP11 ⁺ mCAF is identified, through single‐cell RNA sequencing, which accumulates progressively during bladder cancer progression and is significantly associated with poor prognosis. This cell population regulates the migration of tip endothelial cell clusters (ESM1 ⁺ tEC) via the WNT5A‐MCAM signaling axis, and modulates the expression of key transcription factors, SOX18 , NFIC , and HOXB9 . Additionally, MMP11 ⁺ mCAFs recruit SPP1 ⁺ macrophages through CCL11/CCL2, promoting VEGFA secretion, which further enhances the pro‐angiogenic activity of ESM1 ⁺ tECs. Furthermore, interferon‐associated basal‐like tumor cells secrete BMP2, which induces the expression and activity of NFE2L3, a transcription factor specific to MMP11 ⁺ mCAFs, promoting WNT5A expression. Mouse experiments confirmed that inhibiting BMP2 can suppress tumor angiogenesis and growth in bladder cancer. Pan‐cancer analysis revealed that MMP11 ⁺ mCAFs are present across various cancer types, including breast cancer, lung adenocarcinoma, gastric cancer, and colorectal cancer. These findings provide insights into the heterogeneity of CAFs and their regulatory role in tumor progression, offering new potential therapeutic targets for CAF‐targeted treatments with broad applicability across cancers.