CD301b lectin expression in the breast tumor microenvironment augments tumor growth.

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). 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 through myeloid-tumor interactions. Phenotypic analyses revealed that CD301b(+) cells within tumors are type 2 conventional dendritic cells (cDC2s), a subset known to influence immune polarization. Single-cell RNA sequencing of human breast cancers showed that the human ortholog CLEC10A is expressed in cDC2-like dendritic cells and select macrophage subsets, suggesting a conserved role for CD301(+) myeloid populations. Transcriptomic profiling of tumors developed in Mgl2-deficient mice revealed a shift toward an inflammatory, immune-activated state consistent with enhanced antitumor immunity. Together, these findings establish a link between tumor glycosylation and lectin signaling of myeloid cells, highlighting CD301b as a potential target for reprogramming the tumor immune microenvironment in breast cancer.