Journal of translational medicine · 2026
ICAM-1⁺CD51⁺ CAFs drive immunosuppression in colorectal cancer via OPN-triggered chemokine secretion.
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Liu Jia, Xue Senrui, Xu Yixin, Wu Sicheng, Zhao Wenyu, Li Xinmiao, Hu Nan, Sun Jinmin, Ren Jing
Аннотация
BACKGROUND: 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.
METHODS: 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-1+CD51+CAFs on CRC tumor growth and immune cell infiltration. Cytokine array profiling, western blotting, and bioinformatics analyses were employed to explore the underlying signaling pathways.
RESULTS: 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.
CONCLUSION: 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.
METHODS: 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-1+CD51+CAFs on CRC tumor growth and immune cell infiltration. Cytokine array profiling, western blotting, and bioinformatics analyses were employed to explore the underlying signaling pathways.
RESULTS: 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.
CONCLUSION: 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.