膀胱癌（BC）复发是一个重大的临床挑战，并且通过针对肿瘤微环境（TME）进行治疗是一种有希望的方法。然而，个体TME成分尤其是癌相关成纤维细胞（CAFs）与肿瘤复发之间的关系尚不清楚。本研究利用单细胞RNA测序技术对62,460个细胞进行了初发和复发BC的TME异质性研究。在复发BC中确认了两个癌干细胞（CSC）亚型。还发现了一种炎性CAFs亚型，ICAM1+ iCAFs，与BC复发有特定关联。发现iCAFs能分泌FGF2，FGF2可以作用于rCSC-M的CD44受体，从而维持肿瘤干细胞特性和上皮间质转化。此外，在复发BC中富集了一组单核细胞源性抑制性细胞（MDSCs）——THBS1+单核细胞，它们与CAFs发生相互作用。发现ICAM1+ iCAFs能分泌CCL2，而CCL2则可以与MDSCs上的CCR2结合。此外，iCAFs中升高的STAT3、NFKB2、VEGFA和CTGF水平重新塑造了复发肿瘤的TME。在原位BC小鼠模型中抑制CCL2可以抑制肿瘤生长，减少MDSCs和Tregs，促进肿瘤免疫抑制。研究结果突出了在复发BC中iCAFs在TME细胞间相互作用中的作用。鉴别重要的信号因子有助于推动BC复发的发展，并为新疗法的开发提供有希望的方向。© 2023 The Authors. 由Wiley-VCH GmbH出版的Advanced Science。

Bladder carcinoma (BC) recurrence is a major clinical challenge, and targeting the tumor microenvironment (TME) is a promising therapy. However, the relationship between individual TME components, particularly cancer-associated fibroblasts (CAFs), and tumor recurrence is unclear. Here, TME heterogeneity in primary and recurrent BC is investigated using single-cell RNA sequence profiling of 62 460 cells. Two cancer stem cell (CSC) subtypes are identified in recurrent BC. An inflammatory CAF subtype, ICAM1+ iCAFs, specifically associated with BC recurrence is also identified. iCAFs are found to secrete FGF2, which acts on the CD44 receptor of rCSC-M, thereby maintaining tumor stemness and epithelial-mesenchymal transition. Additionally, THBS1+ monocytes, a group of myeloid-derived suppressor cells (MDSCs), are enriched in recurrent BC and interacted with CAFs. ICAM1+ iCAFs are found to secrete CCL2, which binds to CCR2 in MDSCs. Moreover, elevated STAT3, NFKB2, VEGFA, and CTGF levels in iCAFs reshape the TME in recurrent tumors. CCL2 inhibition in an in situ BC mouse model suppressed tumor growth, decreased MDSCs and Tregs, and fostered tumor immune suppression. The study results highlight the role of iCAFs in TME cell-cell crosstalk during recurrent BC. The identification of pivotal signaling factors driving BC relapse is promising for the development of novel therapies.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.