Gangliosides, sialylated glycosphingolipids abundant in the nervous system, play crucial roles in neurotransmission, interaction with regulatory proteins, cell-cell recognition, and signaling. Altered gangliosides expression has been correlated with pathological processes, including cancer, inflammatory disorders, and autoimmune diseases. Gangliosides are important endogenous ligands of Siglecs (Sialic acid-binding immunoglobulin-type lectins), I-type lectins mostly expressed by immune cells, that specifically recognize sialylated glycans. Siglec-7, an inhibitory immune receptor on human natural killer cells, represents a potential target for tumor immunotherapy. Notably, the expression of Siglec-7 ligands is high in various cancers, such as pancreatic cancer and melanoma and lead to tumor immune evasion. Siglec-7 binds the disialylated ganglioside GD3, a tumor-associated antigen overexpressed on cancer cells to suppress immune responses. Using a combination of structural biology techniques, including Nuclear Magnetic Resonance (NMR), biophysical, and computational methods, the binding of Siglec-7 to GD3 and Gb3 derivatives is investigated, revealing the importance of ligand conformation in modulating binding energetics and affinity. The greater flexibility of Gb3 derivatives appears to negatively impact binding entropy, leading to lower affinity compared to GD3. A thorough understanding of these interactions could contribute to elucidating molecular mechanisms of cancer immune evasion and facilitate the development of ganglioside-based diagnostic and therapeutic strategies for cancer.

CEINGE Biotecnologie Avanzate Franco Salvatore Via Gaetano Salvatore 486 Napoli 80145 Italy

Department of Biochemistry Faculty of Science Charles University Hlavova 2030 8 Prague 12800 Czech Republic

Department of Chemical Sciences University of Naples Federico 2 Via Cinthia 4 Naples 80126 Italy

Department of Chemistry National Tsing Hua University Hsinchu 300044 Taiwan

Department of Medicinal and Applied Chemistry Kaohsiung Medical University Kaohsiung 80708 Taiwan

Giotto Biotech s r l Sesto Fiorentino 50019 Italy

Magnetic Resonance Centre CIRMMP and Department of Chemistry Ugo Schiff University of Florence Via Luigi Sacconi 6 Sesto Fiorentino 50019 Italy

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