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bioRxiv · 10.64898/2026.09.09.749950

Melanoma suppresses galectin-9-glycan axis in dendritic cells and galectin-9 restoration limits T regulatory cell expansion

Rodgers-Furones, A.·Gonzalez de Zarate, A.·Basiakos, T.·Lee, C. Y. C.·van Mierlo, G.·Marino, K. V.·Querol Cano, L.
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Abstract

Dendritic cells (DCs) are key orchestrators of anti-tumor adaptive immune responses. Their function is tightly regulated by galectins, a family of carbohydrate-biding proteins that decode extracellular glycans into intracellular signaling. Here, we show that exposure to melanoma-conditioned media (CM) induces loss of galectin-9 (gal-9) at the DC surface. Notably, gal-9 loss, independent of transcriptional regulation, was associated with the acquisition of an immunosuppressive phenotype in CD14cDC2 cells following tumor exposure, with higher-molecular weight fractions of the melanoma secretome as mediators. Notably, gal-9 depletion was mirrored with a reduction in gal-9 ligands on the cell surface, particularly GalNAc-containing glycoepitopes, pointing towards a melanoma-exploited gal-9-glycan axis as a DC-evasive strategy. Interestingly, restoring gal-9 surface levels in CM-exposed CD14cDC2 cells prevented the expansion of regulatory T cells (Tregs), postulating gal-9 as a novel immunomodulatory molecule in DC-mediated Treg induction during melanoma progression. Altogether, our data suggest that melanoma-derived factors remodel the DC glycan-gal-9 axis to enhance T cell differentiation towards regulatory phenotypes and dampen anti-tumor immunity. This identifies the gal-9/glycan axis in CD14cDC2 cells as a vulnerable node in melanoma immune evasion and as a potential therapeutic target.

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Rodgers-Furones, A., Gonzalez de Zarate, A., Basiakos, T., Lee, C. Y. C., van Mierlo, G., Marino, K. V., Querol Cano, L.. 2026-09-15. Melanoma suppresses galectin-9-glycan axis in dendritic cells and galectin-9 restoration limits T regulatory cell expansion. https://doi.org/10.64898/2026.09.09.749950

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