Precision Targeted Therapy for Bladder Cancer Reaches a New Milestone: Professor Xu Tao’s Team from Peking University People’s Hospital Demonstrates Potent Synergistic Effects Through Combination Treatment

Editor’s Note : Bladder cancer is one of the most common malignant tumors of the genitourinary system. In recent years, the emergence of antibody-drug conjugates (ADCs) has brought new hope for patients with advanced bladder cancer. Among them, Enfortumab Vedotin (EV) — an ADC targeting the tumor antigen Nectin-4 — has been hailed as a “precision-guided missile.” However, the molecular mechanisms underlying the variability in EV’s therapeutic response have not been fully elucidated.

Recently, Professor Xu Tao’s research team from the Department of Urology at Peking University People’s Hospital published a study in Cancer Research titled “Targeting Sialylation Enhances the Therapeutic Efficacy of the Nectin-4-Targeted Antibody-Drug Conjugate Enfortumab Vedotin in Bladder Cancer.” The paper provides an in-depth exploration of key molecular determinants that influence the efficacy of EV in bladder cancer and reveals novel mechanistic insights. The researchers discovered that the glycosylation phenotype of tumor cells significantly affects the anti-tumor activity of EV — findings that hold important clinical implications.

Decoding the Mechanism: How Glycosylation Shapes Drug Response

As a new-generation anti-cancer therapy, ADCs combine the precision of targeted therapy with the cytotoxic potency of traditional chemotherapy. Clinical trials have shown encouraging outcomes, with response rates closely linked to the level of target expression on tumor cells.

Previous studies indicate that most bladder cancer patients with Nectin-4 amplification respond well to EV, whereas only a small subset of patients without Nectin-4 amplification show any benefit. Moreover, EV — which delivers the microtubule inhibitor monomethyl auristatin E (MMAE) — also exerts an immunomodulatory effect by inducing immunogenic cell death (ICD), providing a strong biological rationale for combining EV with immunotherapy.

Tumor cells often exhibit hyperglycosylated phenotypes, which profoundly influence their biological behaviors. Among different glycosylation types, N-glycosylation plays a central role and can be classified into high-mannose, hybrid, and complex forms. These structures are synthesized in a defined sequence by various glycosyltransferases and glycosidases.

Sialic acids, typically located at the terminal ends of glycan chains, are recognized by receptors such as Siglecs expressed on immune cells and generally act as immune suppressors within the tumor microenvironment.

Key Findings: Sialylation Dampens the Anti-Tumor Activity of EV

The study revealed that Nectin-4 expression in bladder tumor cells is positively correlated with the abundance of high-mannose N-glycans, but negatively correlated with complex-type N-glycans and sialylated glycans.

A high-sialylation phenotype was found to impair the efficacy of EV through multiple mechanisms:

Promoting degradation of Nectin-4, reducing the availability of target binding sites.

Inhibiting EV internalization, thereby diminishing intracellular drug delivery.

Suppressing EV-induced immunogenic cell death (ICD), leading to reduced immune activation.

Building upon these insights, the researchers used a sialyltransferase inhibitor (P-3Fax-Neu5Ac) in both in vitro and in vivo models. The combination markedly enhanced tumor sensitivity to EV monotherapy and further potentiated the efficacy of the EV + immunotherapy regimen.

These findings highlight tumor-intrinsic sialylation as a promising therapeutic target to improve the response to ADCs in bladder cancer and provide new perspectives for personalized, precision medicine.

Author Information

Co-first authors:

Dr. Wu Jilin, Department of Urology, Peking University People’s Hospital

Dr. Cheng Bisheng, Department of Urology, Nanfang Hospital, Southern Medical University

Co-corresponding authors:

Professor Xu Tao, Department of Urology, Peking University People’s Hospital

Associate Professor Qin Caipeng, Department of Urology, Peking University People’s Hospital

Associate Researcher Du Yiqing, Department of Urology, Peking University People’s Hospital

Contributors: Dr. Song Yuxuan, Dr. Cheng Jiahui, Dr. Gao Hanlin, and Dr. Luo Xing provided key support in the study.

This research was supported by the National Key R&D Program of China, the National Natural Science Foundation of China, the Beijing Municipal Science & Technology Commission, and the Research and Development Fund of Peking University People’s Hospital.

Corresponding Authors: