Targeting Sialidase to PD1 Enhances T cell Function and Tumor Control.

Immune therapies targeting the PD1 axis have transformed outcomes in cancer treatment by enhancing T cell-mediated immune responses. However, many tumors evade immune clearance through orthogonal escape mechanisms. Excessive production of immunosuppressive sialic acid-containing glycans (sialoglycans) can impair immune surveillance by recruiting inhibitory Siglecs to the immune synapse where, like PD1, they act as checkpoints for cell activation. Sialic acids can also impact T cell activation by dampening the ligation of the costimulatory receptor CD28 with its ligands. This polypharmacology implicates sialoglycans as a linchpin of tumor immunity that can be targeted to further improve outcomes of PD1 therapies. In this work we conjugated sialidase to anti-PD1 (αPD1-S) to selectively degrade sialic acids on immune cells expressing PD1. Glycan profiling confirmed targeted desialylation, and functional assays demonstrated enhancements to T cell activation and cytotoxic capacity. In a melanoma model, αPD1-S promoted inflammatory macrophage polarization and reduced T cell exhaustion, collectively restricting melanoma growth beyond anti-PD1 (αPD1) alone. By simultaneously blocking PD1 and degrading sialoglycans, αPD1-S provides a novel strategy to enhance T cell-mediated immune responses and improve tumor control in refractory cancers.