Sialic acid-binding immunoglobulin-type lectin–sialoglycan axis (Siglec–sialoglycan axis) (Siglec–sialoglycan axis)

The Sialic acid-binding immunoglobulin-type lectin (Siglec)–sialoglycan axis is a critical glyco-immune checkpoint that regulates immune cell activity through the recognition of sialic acid-containing glycans (sialoglycans). In a physiological context, this axis functions as a 'self-recognition' system where inhibitory Siglecs on immune cells bind to sialoglycans on host tissues to maintain immune tolerance and prevent autoimmunity [2, 8]. However, many cancers exploit this pathway by overexpressing sialic acids—a phenomenon known as hypersialylation—which creates an immunosuppressive shield that dampens the activity of natural killer (NK) cells, T cells, and macrophages [4, 6]. By engaging inhibitory Siglecs, tumor cells effectively evade immune surveillance, mirroring the mechanisms of the well-established PD-1/PD-L1 checkpoint [1, 10]. Therapeutic interventions targeting this axis are currently in clinical development and include monoclonal antibodies that block specific Siglec receptors, antibody-drug conjugates for targeted cell killing, and innovative sialidase-based biologics designed to strip the tumor surface of its protective sialic acid layer [3, 7, 9]. This axis represents a promising target for next-generation immunotherapies, particularly for patients who do not respond to existing checkpoint inhibitors [5, 13].

Other names

Siglec-sialoglycan pathwayGlyco-immune checkpointSialic acid-Siglec axisSialoside-Siglec axisSialoglycan-Siglec checkpoint

Drugs targeting this axis primarily work through: 1) Antagonistic blockade of inhibitory Siglec receptors (e.g., Siglec-15, Siglec-7, Siglec-9) to restore immune cell effector function; 2) Enzymatic desialylation of the tumor glycocalyx using sialidase fusion proteins to remove the immunosuppressive 'self' signal; 3) Targeted depletion of Siglec-expressing malignant cells using antibody-drug conjugates (ADCs) or immunotoxins; and 4) Agonistic activation of inhibitory Siglecs to suppress overactive immune responses in autoimmune or inflammatory conditions [1, 3, 7, 9].