Sialoglycan–Siglec inhibitory axis (Siglec axis)

The Sialoglycan–Siglec inhibitory axis is a critical glyco-immune checkpoint that regulates immune cell activity, particularly within the tumor microenvironment. Cancer cells frequently exhibit hypersialylation, where an overabundance of sialic acid-containing glycans (sialoglycans) on their surface interacts with Sialic acid-binding immunoglobulin-type lectin (Siglec) receptors—such as Siglec-7, Siglec-9, and Siglec-15—expressed on T cells, NK cells, and myeloid cells [1, 9, 16]. This interaction typically triggers inhibitory signaling through immunoreceptor tyrosine-based inhibitory motifs (ITIMs), leading to immune evasion by suppressing T cell activation and effector functions [9, 18]. Therapeutic strategies targeting this axis include sialidases (e.g., E-602) that enzymatically strip sialoglycans from the cell surface and monoclonal antibodies (e.g., NC318, PYX-106) that block specific Siglec receptors [1, 3, 8]. These approaches aim to restore the anti-tumor immune response and are currently being investigated in clinical trials for various solid tumors, including non-small cell lung cancer and melanoma [12, 13]. The axis is particularly notable as a potential target for patients who are resistant to traditional PD-1/PD-L1 inhibitors, as Siglec-15 expression is often mutually exclusive with PD-L1 [3, 7].

Other names

Sialic acid–Siglec axisGlyco-immune checkpointSiglec-sialoglycan pathwaySialic acid-binding immunoglobulin-type lectin axis

Therapeutic intervention in this axis occurs through three primary mechanisms: enzymatic desialylation of the tumor surface using sialidases to prevent receptor engagement, monoclonal antibody-mediated blockade of inhibitory Siglec receptors (e.g., Siglec-15, Siglec-7, Siglec-9) to restore immune cell activation, and targeted delivery of cytotoxic payloads via Siglec-mediated endocytosis in malignant cells [1, 5, 9, 16].