Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

Simple Summary Aberrant glycosylation is a common feature of many cancers, and it plays crucial roles in tumor development and biology. Cancer progression can be regulated by several physiopathological processes controlled by glycosylation, such as cell-cell adhesion, cell-matrix interaction, epithelial-to-mesenchymal transition, tumor proliferation, invasion, and metastasis. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs), which are suitable for selective cancer targeting, as well as novel antitumor immunotherapy approaches. This review summarizes the strategies developed in cancer immunotherapy targeting TACAs, analyzing molecular and cellular mechanisms and state-of-the-art methods in clinical oncology. Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control.