Hyperglycosylated cancer cells are often decorated with abundant sialic acids, which are recognized by Sialic acid binding immunoglobulin type lectins (Siglecs) expressed on immune cells. As sialic acids are normally expressed on almost all cell types, Siglecs can function as receptors for “self”. Presently, 15 human Siglecs (including non-sialic acid binding Siglec XII) are known, of which most are immunoinhibitory receptors that induce strong inhibitory signaling when Siglecs bind sialic acids. Hence, tumor cells use hyper sialic acid expression in their favor to modify the immune system that can lead to immune suppression. Such engagement along the Siglec-sialic acid axis can dampen major killing modes of effector immune cells and suppress the activation of immune responses, which can lead to immune tolerance and tumor growth. In this review, we emphasized recent studies on all 15 Siglecs found in humans, many of which still remain understudied. In addition, we highlighted different strategies in disrupting the surface Siglec-sialic acid interactions, including antibodies and glycan moieties, which can steer back antitumor immune responses to reduce tumor size and improve overall survival of cancer patients.

Hypersialylation is a common post-translational modification of protein and lipids found on cancer cell surfaces, which participate in cell-cell interactions and in the regulation of immune responses. Sialic acids are a family of nine-carbon α-keto acids found at the outermost ends of glycans attached to cell surfaces. Given their locations on cell surfaces, tumor cells aberrantly overexpress sialic acids, which are recognized by Siglec receptors found on immune cells to mediate broad immunomodulatory signaling. Enhanced sialylation exposed on cancer cell surfaces is exemplified as “self-associated molecular pattern” (SAMP), which tricks Siglec receptors found on leukocytes to greatly down-regulate immune responsiveness, leading to tumor growth. In this review, we focused on all 15 human Siglecs (including Siglec XII), many of which still remain understudied. We also highlighted strategies that disrupt the course of Siglec-sialic acid interactions, such as antibody-based therapies and sialic acid mimetics leading to tumor cell depletion. Herein, we introduced the central roles of Siglecs in mediating pro-tumor immunity and discussed strategies that target these receptors, which could benefit improved cancer immunotherapy.