Tumor-secreted galectin-3 suppresses antitumor response by inducing IL-10 B cells.

BACKGROUND

Breast cancer is the leading cause of cancer-related deaths among women globally. Tumor-secreted proteins foster an immunosuppressive environment, enabling immune evasion and reducing the effectiveness of antitumor immunity. Interleukin (IL)-10, an immune-regulatory cytokine, is upregulated in breast cancer (BRCA), but the underlying mechanism remains unclear.

METHODS

analysis was used to identify candidate genes associated with IL-10 expression. Mouse model of BRCA and co-culture assays were conducted to identify immune cells responsible for IL-10 upregulation. The efficacy of galectin-3 (Gal-3) inhibition combined with chemotherapy was also evaluated.

RESULTS

Tumor-secreted Gal-3 served as a key immunosuppressive factor in BRCA. Gal-3 promoted IL-10 production in B cells, thus impairing antitumor immunity. Mechanistically, Gal-3 triggered CD45 polymerization, reducing its phosphatase activity and subsequently activating STAT3 to promote IL-10 production. Knockdown of STAT3 or its blockade abrogated Gal-3-induced IL-10 upregulation. Furthermore, Gal-3 inhibition combined with chemotherapy significantly reduced tumor growth and enhanced antitumor immunity.

CONCLUSIONS

Gal-3 is a crucial regulator of immune evasion in BRCA. Targeting Gal-3 may improve the efficacy of BRCA therapies.