Cancer Communications | Targeting MAN1B1 Enhances Bladder Cancer Antitumor Immunity via Deglycosylation of CD47

This study elucidates the mechanism by which MAN1B1 enhances tumor immune escape in bladder cancer through CD47 glycosylation regulation and identifies its inhibitor as an effective promoter of macrophage phagocytosis without inducing anemia, providing a novel target for immunotherapy.

 

Literature Overview
The article 'Targeting MAN1B1 potently enhances bladder cancer antitumor immunity via deglycosylation of CD47' published in Cancer Communications reveals that abnormal CD47 glycosylation plays a critical role in bladder cancer immune escape. It identifies MAN1B1 as the primary glycosyltransferase whose stability is regulated by ERK-HRD1 interaction. The research demonstrates that MAN1B1 knockout or inhibition significantly reduces CD47-SIRP-α binding, enhancing macrophage phagocytosis without anemia, offering a safer alternative strategy for anti-CD47 therapy.

Background Knowledge
CD47, an immune checkpoint protein highly expressed on various tumor cell surfaces, delivers 'don't eat me' signals via SIRP-α binding on macrophages, suppressing phagocytosis and enabling immune escape. Current anti-CD47 monoclonal antibodies in clinical trials for hematologic malignancies and solid tumors face limitations due to CD47's widespread expression in red blood cells and platelets, causing anemia-related side effects.
Identifying upstream regulators of CD47 glycosylation, particularly tumor-specific enzymes, has become crucial for improving antitumor immunotherapy. MAN1B1, an α-mannosidase involved in N-glycosylation modification, is overexpressed in bladder cancer tissues. ERK-HRD1 pathway stabilizes MAN1B1 through inhibition of ubiquitination degradation, promoting CD47 glycosylation and enhancing SIRP-α binding to facilitate immune escape. This study further validates that MAN1B1 inhibitor DHT I significantly enhances phagocytic activity in preclinical models, providing a theoretical basis for non-anemic immunotherapeutic strategies.

 

 

Research Methods and Experiments
The research team analyzed CD47 glycosylation status and its binding capacity with SIRP-α using Western blot, immunohistochemistry, and flow cytometry. CRISPR/Cas9 technology was employed to construct MAN1B1-knockout bladder cancer cell lines, with phagocytic effects evaluated in vitro and in vivo. Additional methodologies included molecular docking, protein interaction analysis, mouse xenograft models, and patient-derived tumor organoid models for functional validation.

Key Conclusions and Perspectives

• CD47 exhibits extensive glycosylation in bladder cancer, where glycosylation is essential for SIRP-α binding.
• MAN1B1 serves as the critical enzyme for CD47 glycosylation modification, showing significantly elevated expression in bladder cancer tissues.
• Aberrant ERK activation stabilizes MAN1B1 by inhibiting HRD1-mediated ubiquitination degradation, thereby promoting CD47 glycosylation.
• MAN1B1 knockout or inhibition by DHT I dramatically enhances macrophage phagocytosis without inducing anemia.
• In NSG mouse models, MAN1B1 deficiency suppresses tumor growth and enhances phagocytic functions of tumor-associated macrophages.

Research Significance and Prospects
This study first identifies MAN1B1 as a key regulator in CD47 glycosylation, proposing it as a novel immunotherapy target that circumvents anemia associated with CD47-targeted therapies. Future investigations should evaluate MAN1B1 inhibitor efficacy across tumor types and explore its application in combination with immune checkpoint inhibitors.

 

 

Conclusion
Through multi-omics and functional experiments, this study systematically reveals the role of MAN1B1 in bladder cancer immune escape. CD47 glycosylation status critically determines its 'don't eat me' signaling, while MAN1B1 expression and stability are regulated by the ERK-HRD1 pathway. Targeting MAN1B1 effectively enhances macrophage-mediated phagocytosis while avoiding anemia-related side effects of CD47-targeting therapies, offering new molecular targets and therapeutic strategies for bladder cancer and other solid tumors. Future studies should explore synergistic effects of MAN1B1 inhibitors with immune modulators and assess their safety and efficacy in preclinical models.

 

Jie Zhang, Chen Zhang, Ruichen Zang, Yanlan Yu, and Guoqing Ding. Targeting MAN1B1 potently enhances bladder cancer antitumor immunity via deglycosylation of CD47. Cancer Communications.