Myeloid Lectin Profiling Identifies SYK as a Targetable Signaling Node for Remodeling Immunosuppressive Tumor-Associated Macrophages in Breast Cancer

Immunosuppressive environments in breast cancer tumors hinder immune response and treatment efficacy. Key players in this suppression are myeloid-driven inflammation from tumor-associated macrophages (TAMs). TAMs express lectins, which are glycan-sensing receptors that drive immune suppression. However, it was unclear if specific myeloid lectins define TAM states or if their signaling could be targeted pharmaceutically.

A study examined immunosuppressive tumors from 3207 patients, focusing on differential expression, single-cell localization, and immune-related regulators. This analysis revealed a panel of 12 lectins associated with immunosuppressive tumors. A 3D model of the immunosuppressive TME, composed of BC spheroids, fibroblasts, and blood-derived macrophages, was used to probe this lectin panel.

Eight lectins were found to be highly expressed, with four being upregulated in TAMs. Poorer survival outcomes were linked to the expression of CLEC4E/Mincle, CLEC6A/Dectin-2, and CD209/DC-SIGN. Further investigation identified CLEC4E and CLEC6A as converging on the FcR{gamma}/SYK signaling pathway, making this shared node a target for pharmacological intervention.

R406 reduced SYK phosphorylation, induced transcriptional remodeling in TAMs, and altered immunosuppressive macrophage features. These results define a myeloid lectin framework linked to breast cancer immunosuppression and identify SYK as a potential target for TAM remodeling.