Dectin-1 signaling promotes Galectin-3 shedding and expansion of immunosuppressive CD71+ erythroid cells in breast cancer.

Immunotherapy with immune checkpoint inhibitors (ICIs) has transformed cancer treatment, yet many patients fail to respond, underscoring the need to better understand mechanisms of resistance. One emerging mechanism involves the recruitment of erythroid progenitors and precursors, known as CD71+ erythroid cells (CECs), to the tumor microenvironment. Using murine models of triple-negative breast cancer (TNBC), we investigated the therapeutic effects of curdlan, a β-glucan. We found that TNBC was associated with extramedullary erythropoiesis and expansion of CECs. Unexpectedly, curdlan worsened tumor progression by further increasing CEC abundance. Immunophenotypic analysis revealed a marked expansion of Galectin-3 (Gal-3)+ CECs in both spleen and tumor. Mechanistically, our findings suggest that curdlan-Dectin-1ligation induces Gal-3 shedding from CD11b+cells, enabling its deposition onto CECs. Notably, we discovered that Gal-3 is co-expressed and colocalized with PD-L1 and Dectin-1 on CECs. Importantly, PD-L1 blockade substantially reduced immunosuppressive Gal-3+PD-L1+ CECs, suppressed extramedullary erythropoiesis, and induced pronounced tumor regression. Re-analysis of publicly available scRNAseq datasets further confirmed the abundance of Gal-3+ CECs in human bone marrow. Collectively, these findings identify Gal-3+PD-L1+ CECs as key drivers of an immunosuppressive tumor microenvironment and reveal a previously unrecognized axis through which PD-L1 blockade exerts therapeutic benefit in breast cancer.