Polysialylated CD56 drives immune evasion in clear cell renal cell carcinoma via engagement of the Siglec-7 checkpoint on CD8+ T cells

Immune checkpoint blockade has revolutionized clear cell renal cell carcinoma (ccRCC) treatment, yet therapeutic resistance remains a significant clinical challenge. Aberrant glycosylation contributes to tumor progression and immunotherapy resistance. However, the specific glycans and corresponding immunomodulatory receptors involved in ccRCC remain poorly understood. Here, we identify polysialylated CD56 (PSA-CD56) as a key glycan-mediated immune regulator that drives immunosuppression in ccRCC through engagement of Siglec-7. Elevated PSA-CD56 expression was inversely correlated with CD8⁺ T cell infiltration and predicted inferior responses to immunotherapy. Genetic ablation of NCAM1 (encoding CD56) in renal epithelial cells suppressed tumor growth and enhanced CD4⁺ and CD8⁺ T cell infiltration in vivo. Mechanistically, PSA-CD56, but not its non-polysialylated form, directly bound to Siglec-7 on CD8⁺ T cells, suppressing the production of IFN-γ and TNF-α and promoting T cell apoptosis. Importantly, blocking the PSA-CD56/Siglec-7 interaction with specific antibodies restored T cell effector functions and triggered apoptosis of ccRCC cells. Our study unveils the PSA-CD56/Siglec-7 axis as a novel glyco-immune checkpoint, which represents a promising target for therapeutic interventions in ccRCC.