ICAM-1⁺CD51⁺ CAFs drive immunosuppression in colorectal cancer via OPN-triggered chemokine secretion

Abstract 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.