结直肠癌（CRC）是临床常见的恶性肿瘤之一，也是世界上第四大癌症相关死亡原因。肿瘤微环境（TME）在促进肿瘤血管生成中发挥着至关重要的作用，而癌症相关成纤维细胞（CAF）是肿瘤微环境的关键组成部分之一。然而，由于CAF的高度异质性，阐明CAF介导的肿瘤血管生成的分子机制仍然难以捉摸。在我们的研究中，我们发现结直肠癌中 CAF 存在促血管生成功能异质性，并且我们阐明了 Podoplanin (PDPN) 可以特异性标记具有促血管生成功能的 CAF 亚群。我们还发现PDPN  CAF可以通过自分泌CCL2形成PDPN/CCL2/STAT3反馈环来维持CAF异质性，同时通过旁分泌CCL2激活内皮细胞中的STAT3信号通路以促进血管生成。我们证明 WP1066 可以通过阻断 CAF 中的 PDPN/CCL2/STAT3 反馈环路和内皮细胞中的 STAT3 信号通路来抑制结直肠癌血管生成。总而言之，我们的研究表明 STAT3 可能成为阻断结直肠癌血管生成的潜在治疗靶点。我们为结直肠癌的临床治疗提供理论基础和新的治疗策略。© 2024。作者，获得 Springer Nature B.V. 独家许可。

Colorectal cancer (CRC) is one of the common clinical malignancies and the fourth leading cause of cancer-related death in the world. The tumor microenvironment (TME) plays a crucial role in promoting tumor angiogenesis, and cancer-associated fibroblasts (CAFs) are one of the key components of the tumor microenvironment. However, due to the high heterogeneity of CAFs, elucidating the molecular mechanism of CAF-mediated tumor angiogenesis remained elusive. In our study, we found that there is pro-angiogenic functional heterogeneity of CAFs in colorectal cancer and we clarified that Podoplanin (PDPN) can specifically label CAF subpopulations with pro-angiogenic functions. We also revealed that PDPN + CAF could maintain CAF heterogeneity by forming a PDPN/CCL2/STAT3 feedback loop through autocrine CCL2, while activate STAT3 signaling pathway in endothelial cells to promote angiogenesis through paracrine CCL2. We demonstrated WP1066 could inhibit colorectal cancer angiogenesis by blocking both the PDPN/CCL2/STAT3 feedback loop in CAFs and the STAT3 signaling pathway in endothelial cells. Altogether, our study suggests that STAT3 could be a potential therapeutic target for blocking angiogenesis in colorectal cancer. We provide theoretical basis and new therapeutic strategies for the clinical treatment of colorectal cancer.© 2024. The Author(s), under exclusive licence to Springer Nature B.V.