The Tumour Glyco-Code: Sialylation as a Mediator of Stromal Cell Immunosuppression in the Tumour Microenvironment

The tumour microenvironment (TME) comprises a complex interplay of tumour cells, nonmalignant cells (including endothelial, immune, and stromal cells), and secreted factors within the extracellular matrix (ECM). Immunosuppression within the TME significantly hinders the efficacy of cancer immunotherapies. Stromal-rich TMEs, characterised by an abundance of mesenchymal stromal cells (MSCs) and cancer-associated fibroblasts (CAFs), are particularly immunosuppressive and associated with poor responses to conventional and immune-based therapies. Glycans, carbohydrate structures on cell surfaces, are dynamically regulated during tumourigenesis and mediate crucial cell-cell communications through receptor-ligand interactions. Sialylation, the addition of sialic acids to glycans, forms sialoglycans that can engage inhibitory Siglec receptors expressed on immune cells and promote immunosuppressive signalling. Emerging evidence implicates aberrant sialylation in the TME as a key driver of immunosuppression. More recently, sialylation of stromal cells in the TME has been shown to suppress anti-tumor immunity. This review explores the role of sialylation within stromal-rich, immunosuppressive TMEs, focusing on how specific sialic acid/Siglec interactions dictate innate and adaptive immune responses. We discuss the potential of targeting glycoimmune checkpoints to overcome stromal-mediated resistance and enhance anti-tumour immunity.