Targeting Sialylation Enhances the Therapeutic Efficacy of the Nectin-4-Targeted Antibody-Drug Conjugate Enfortumab Vedotin in Bladder Cancer

More than half of advanced or metastatic bladder Cancer (BCa) patients are ineligible for cisplatin chemotherapy or have poor response to cisplatin. Recently, the combination therapy of enfortumab vedotin (EV), a Nectin-4-targeted antibody-drug conjugate (ADC), with the anti-PD-1 antibody pembrolizumab (EV+Pembro) has shown high and durable response rates, as well as survival benefits for these BCa patients. Identifying factors that impact the response to single-agent EV or EV+Pembro therapy could help to further improve response rates. Here, we showed that Nectin-4 expression is negatively correlated with sialylation and complex type N-glycans levels and positively correlated with high-mannose type N-glycans levels in BCa. Pharmacological inhibition of sialylation sensitized BCa to EV monotherapy and its combination with immunotherapy both in vitro and in vivo. Mechanistically, α-2,6-sialylation mediated the downregulation of Nectin-4. Furthermore, the removal of sialylation increased the endocytosis of EV by BCa cells and enhanced EV-mediated immunogenic cell death (ICD). Collectively, these findings suggest that sialylation is a promising therapeutic target to improve EV sensitivity and provide a rational basis for clinical application of sialylation inhibitors in BCa.