Abstract B045: Siglec receptors suppress T cell immunity via trogocytosis and represent degradable targets for cancer immunotherapy

Abstract Cancer therapy has been rapidly transformed by the development of immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1. However, many patients fail to respond, particularly those with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. To overcome therapeutic resistance, identifying and targeting new types of checkpoints, such as glycan-binding immune checkpoints, may offer a promising strategy to reprogram the TME by suppressing tumor-promoting factors. Sialic acid-binding immunoglobulin-like lectin (Siglec) receptors, especially the inhibitory members constitutively expressed on myeloid cells, play an immunosuppressive role in innate immunity. Here, we identify Siglec-7 and -9 immunosuppressors as novel glyco-immune checkpoints that inhibit T cell function and anti-tumor immunity. We discovered that T cells in the TME acquire these Siglec checkpoints from myeloid cells via trogocytosis, impairing T cell activity by dephosphorylating T cell receptor (TCR)-related signaling pathways through engagement with tumor-associated sialoglycans. Using sulfur(VI) fluoride exchange (SuFEx) click chemistry, we developed a high-affinity ligand specific for Siglec-7 and -9, and converted it into a degrader for targeted lysosomal degradation of both Siglecs. This degrader efficiently reduced Siglec levels in T cells and myeloid cells, significantly restoring T cell function and enhancing anti-tumor immunity. The degrader, particularly when combined with anti-CTLA-4, reshaped the TME and generated durable T cell memory, resulting in excellent tumor control in multiple murine models. These findings underscore the significance of degrading exogenously acquired Siglec checkpoints on T cells as a novel strategy to overcome resistance to established checkpoint inhibitors in cancer immunotherapy. Citation Format: Chao Wang. Siglec receptors suppress T cell immunity via trogocytosis and represent degradable targets for cancer immunotherapy [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B045.