Sialic acid cis-ligands as modulators of Siglec function in cancer immunity

The Siglec-sialoglycan axis is an emerging glyco-immune checkpoint in cancer. This is supported by the frequent upregulation of both Siglecs and sialoglycans in the tumor microenvironment. Siglecs are receptors expressed on immune cells that recognize sialoglycans, carbohydrate structures terminated by sialic acid. Most Siglec receptor family members are inhibitory and suppress immune cell activation through the recruitment of SHP-1 and SHP-2 phosphatases. It is well established that Siglecs expressed by immune cells bind ligands present on other cells, including tumor and stromal cells (trans-interactions). However, immune cells themselves also express sialoglycans that can serve as ligands for Siglecs on the same cell surface (cis-interactions). Over the past two decades, numerous studies have addressed how Siglec trans-engagement facilitates immunosuppression in the tumor microenvironment. The role of cis-interactions in regulating Siglec function and their impact on immune cell activity, however, remains an underexplored topic for most Siglec family members. This review discusses how cis-ligands modulate Siglec function, the mechanisms regulating sialic acid expression on immune cell surfaces, and the functional relevance of cis-interactions expressed by immune cells in the tumor microenvironment. A better understanding of these processes may facilitate the development of next-generation therapeutics targeting the Siglec-sialoglycan axis in cancer.