ICAM-1⁺CD51⁺ CAFs通过OPN触发的趋化因子分泌驱动癌症的免疫抑制
ICAM-1⁺CD51⁺ CAFs drive immunosuppression in colorectal cancer via OPN-triggered chemokine secretion.
摘要(中文译文)
癌症相关成纤维细胞（CAFs）通过免疫抑制促进结直肠癌（CRC）进展，但其功能异质性及募集髓系细胞的具体机制仍不明确。我们运用功能筛选、转录组学和生物信息学分析，鉴定出CRC中具有不同单核细胞募集能力的功能富集CAF亚群。表面标志物通过免疫荧光、免疫组织化学和流式细胞术进行验证。通过体外共培养和体内肿瘤模型研究了所鉴定CAF亚群的作用。利用动物模型研究ICAM-1⁺CD51⁺CAFs对CRC肿瘤生长和免疫细胞浸润的影响。采用细胞因子芯片分析、蛋白质印迹和生物信息学分析探讨其潜在信号通路。我们鉴定出一个由ICAM-1和CD51共表达定义的功能富集CAF亚群（ICAM-1⁺CD51⁺ CAFs），该亚群具有强大的单核细胞募集能力，并驱动单核细胞获得M2样肿瘤相关巨噬细胞（TAMs）和单核细胞型髓源性抑制细胞（M-MDSCs）相关表型及抑制性特征。在临床CRC样本中，ICAM-1⁺CD51⁺ CAFs的丰度与瘤内TAM浸润呈正相关。体内验证证实ICAM-1⁺CD51⁺ CAFs促进TAMs和MDSCs在瘤内积聚，从而加速肿瘤进展。机制上，骨桥蛋白（OPN）与CD51整合素结合激活CAFs内的FAK/p38 MAPK通路，增强关键细胞因子MCP-3、CXCL5和IL-6的分泌，这些细胞因子协调髓系细胞的募集和分化。我们的研究表明，ICAM-1⁺CD51⁺ CAFs通过OPN/CD51-FAK/p38 MAPK轴调控细胞因子分泌，并促进CRC中髓系细胞的募集和分化。靶向该CAF亚群可能代表一种有前景的CRC治疗策略，值得进一步研究。
Abstract
Cancer-associated fibroblasts (CAFs) promote colorectal cancer (CRC) progression through immunosuppression, but their functional heterogeneity and specific mechanisms in recruiting myeloid cells remain poorly defined. Using functional screening, transcriptomics, and bioinformatics analyses, we identified functionally enriched CAF subsets with differing monocyte-recruiting capacities in CRC. Surface markers were validated via immunofluorescence, immunohistochemistry, and flow cytometry. The role of the identified CAF subset was examined using in vitro co-culture and in vivo tumor models. Animal models were utilized to study the impact of ICAM-1CD51CAFs on CRC tumor growth and immune cell infiltration. Cytokine array profiling, western blotting, and bioinformatics analyses were employed to explore the underlying signaling pathways. We identified a functionally enriched CAF subset defined by co-expression of ICAM-1 and CD51 (ICAM-1⁺CD51⁺ CAFs), which exhibits potent monocyte-recruiting capacity and drives monocytes to acquire M2-like tumor-associated macrophages (TAMs) and monocytic myeloid-derived suppressor cells (M-MDSCs) associated phenotype and suppressive feature. In clinical CRC samples, the abundance of ICAM-1⁺CD51⁺ CAFs correlated positively with intratumoral TAM infiltration. In vivo validation confirmed that ICAM-1⁺CD51⁺ CAFs promote intratumoral accumulation of both TAMs and MDSCs, thereby accelerating tumor progression. Mechanistically, osteopontin (OPN) engagement of CD51 integrin activated the FAK/p38 MAPK pathway within CAFs, enhancing secretion of key cytokines MCP-3, CXCL5, and IL-6, which orchestrate myeloid cell recruitment and differentiation. Our study demonstrates that ICAM-1⁺CD51⁺ CAFs regulate cytokine secretion and contribute to myeloid cell recruitment and differentiation in CRC through the OPN/CD51-FAK/p38 MAPK axis. Targeting this CAF subset may represent a promising therapeutic strategy for CRC, which warrants further investigation.
如何引用
AMA
Jia Liu, Senrui Xue, Yixin Xu, Sicheng Wu, Wenyu Zhao, Xinmiao Li, et al. ICAM-1⁺CD51⁺ CAFs drive immunosuppression in colorectal cancer via OPN-triggered chemokine secretion.. Journal of translational medicine. 2026; doi:10.1186/s12967-026-08642-9.
APA
Jia Liu, Senrui Xue, Yixin Xu, Sicheng Wu, Wenyu Zhao, Xinmiao Li, et al (2026). ICAM-1⁺CD51⁺ CAFs drive immunosuppression in colorectal cancer via OPN-triggered chemokine secretion.. Journal of translational medicine. https://doi.org/10.1186/s12967-026-08642-9
GB/T 7714
Jia Liu, Senrui Xue, Yixin Xu, Sicheng Wu, Wenyu Zhao, Xinmiao Li, et al. ICAM-1⁺CD51⁺ CAFs drive immunosuppression in colorectal cancer via OPN-triggered chemokine secretion.[J]. Journal of translational medicine, 2026 doi:10.1186/s12967-026-08642-9.
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