Tumor glycosylation engages CD301b-mediated myeloid regulation in breast cancer

Aberrant tumor glycosylation can alter immune recognition; however, the specific influence of glycan-lectin interactions on tumor progression remains poorly understood. Here, we identify the C-type lectin receptor CD301b (encoded by Mgl2) as a regulator of immune activity within the breast tumor microenvironment (TME) and identify a cross-species myeloid regulatory program associated with its human ortholog CLEC10A. Using a murine triple-negative breast cancer model, we demonstrate that tumors expressing the Tn glycoantigen grow more rapidly, and this growth is facilitated by CD301b⁺ immune cells. Depletion or genetic loss of CD301b markedly suppressed tumor growth, indicating that CD301b promotes tumor progression, potentially through myeloid-tumor interactions. Phenotypic analyses revealed that tumor-infiltrating CD301b⁺ cells are predominantly type 2 conventional dendritic cells (cDC2s) and exhibit IL-10 expression within the TME. Transcriptomic profiling of tumors developed in Mgl2-KO mice revealed a shift toward an inflammatory, interferon-dominant transcriptional state, consistent with altered antitumor immune programming. Single-cell RNA sequencing of human breast cancers revealed that CLEC10A is expressed in cDC2 and select macrophage subsets. Additionally, CLEC10A-positive cDC2 and macrophages share a transcriptional state characterized by enhanced antigen presentation and immune-regulatory functions compared to CLEC10A-negative cells. Together, these findings support a relationship between tumor glycosylation and CLEC10A/CD301b-associated myeloid regulation, highlighting this axis as a potential target for reprogramming the breast tumor immune microenvironment.