Tumor Glycan-Targeted Therapy  

Glycosylation is a sophisticated type of post-translational modification that impacts over 50% of cellular proteins and is a critical regulator of many eukaryotic processes. Aberrant glycosylation is a common hallmark of many malignancies and is important at all stages of tumor growth. Glycosylation regulates a range of physiopathological processes, including cell-cell adhesion, cell-matrix interactions, epithelial-mesenchymal transition, tumor proliferation, invasion, metastasis, and angiogenesis.

Different mechanisms of aberrant glycosylation result in the production of tumor-associated glycoantigens (TACAs), which are useful for tumor-targeted therapy. Truncated O-glycans (Tn, TF, and sialic acid Tn antigens), gangliosides (GD2, GD3, GM2, GM3, and rockulose-GM1), globular serine glycans (globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid are the most well-studied TACAs.

These TACAs have shown potential applications in cancer immunotherapy strategies in past decades. Glycans can serve as a source for the development of novel clinical biomarkers that provide a range of specific targets for therapeutic intervention. At the same time, TACA can interact with antigen-presenting cells through interactions with glycan-binding receptors (e.g. SIGLECs, MGL, DC-SIGN) to induce immunosuppressive signals. There are various therapeutic approaches involving TACA, including vaccine-induced active immunity, as well as genetically engineered development of monoclonal antibodies. More recently, bispecific antibodies and chimeric antigen receptor T (CAR-T) cells, including those for anti-TACA, have been evaluated in the clinic and have made impressive progress.

Targeting GSL

Sphingolipids (GSLs) consist of a heterogeneous group of membrane lipids formed by the ceramide backbone covalently linked to the glycan fraction through β-glycosidic bonds. GSLs are universal cell membrane components that are especially prevalent on the surface of animal cells and have a crucial function in molecular signaling, cell adhesion, and motility. They are classified into three major series in vertebrate tissues: globular, ganglionic, and neoarteritis.

Globo H, SSEA-3, and SSEA-4 are major GSLs defined by TACA, as are sialic acid-containing sphingolipids such as gangliosides GD2, GD3, GM2, rockulosyl GM1, and Neu5GCM3. These GSLs can influence cancer progression by regulating cell adhesion, motility, and proliferation, as well as epithelial-mesenchymal transition, metastasis, and drug resistance.

Targeting mucin-type O-glycan antigen

Simple mucin-type O-glycosylated TACAs, such as Tn antigen (CD175), TF antigen (CD176), and sialic acid Tn antigen (STn, CD175s), are very attractive targets for antitumor therapy because they are detected in most cancers and are not usually present in healthy tissues.

Targeted polysalivary acid

The process of polysaccharide modification attaches monomeric sialic acid entities to the non-reducing end of the polysaccharide to form polysialic acid (PSA). Although PSA is virtually absent in most adult tissues, it is expressed in the progression of several malignancies such as neuroblastoma, breast cancer, laryngeal squamous cell carcinoma, pancreatic cancer, non-small cell lung cancer, and small cell lung cancer. The most important physical property of PSA is its anti-adhesive effect, which facilitates invasion and metastasis, and in addition, the interaction of PSA with suppressive siglec promotes tumor cells' immune escape.

CAR-T cell therapy

In an MHC-independent manner, CAR-T cells combine the specificity of antibodies with the cytolytic capacity of T cells. As a result, a variety of TACAs have been demonstrated to have potential applications for antitumor CAR-T cell therapy, with the most prominent advancements including anti-GD2, anti-MUC1/MUC1-Tn, and anti-STn CAR-T therapies.