Abstract 7288: Targeted degradation of mobile immune checkpoints to advance cancer therapy

Abstract Immune checkpoint inhibitors (ICIs) targeting T cell-intrinsic checkpoints, such as CTLA-4 and PD-1, have shown promising outcomes across diverse cancer patient populations. However, resistance to these ICIs remains prevalent, especially in patients with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. To overcome therapeutic resistance, there is an unmet need to identify novel immune checkpoints involved in cancer progression and to develop innovative therapeutic strategies capable of reprogramming the TME by neutralizing tumor-promoting factors. Here, we identify sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and -9 as mobile immune checkpoints acquired by T cells from myeloid cells via trogocytosis in the TME. These trogocytosed Siglec checkpoints suppress T cell activity by dephosphorylating T cell receptor (TCR)-related signaling pathways through engagement with tumor-associated sialoglycans. To target these mobile checkpoints, we leveraged sulfur(VI) fluoride exchange (SuFEx) click chemistry to develop a high-affinity Siglec-7/-9 ligand and converted it into a degrader for 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, remodeled 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 ICIs in cancer therapy. Citation Format: Chao Wang, Yingqin Hou, Jaroslav Zak, Kelli A. McCord, Qinheng Zheng, Shereen Chung, Ruben D. Peraza, James C. Paulson, John R. Teijaro, Xu Zhou, K Barry Sharpless, Je!rey V. Ravetch, Matthew S. Macauley, Peng Wu. Targeted degradation of mobile immune checkpoints to advance cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7288.