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Aberrant glycosylation is a universal feature of cancer cells, and cancer‐associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N‐glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI‐IMS), we identify larger branched α2,6 sialylated N‐glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N‐glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N‐glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P‐3FAX‐Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N‐glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Essentially all cells are covered with a dense coat of different glycan structures/sugar chains, giving rise to the so‐called glycocalyx. Changes in cellular glycosylation are a hallmark of cancer, affecting most of the pathophysiological processes associated with malignant transformation, including tumour immune responses. Glycans are chief macromolecules that define T‐cell development, differentiation, fate, activation and signalling. Thus, the diversity of glycans expressed at the surface of T cells constitutes a fundamental molecular interface with the microenvironment by regulating the bilateral interactions between T‐cells and cancer cells, fine‐tuning the anti‐tumour immune response. In this review, we will introduce the power of glycans as orchestrators of T‐cell‐mediated immune response in physiological conditions and in cancer. We discuss how glycans modulate the glyco‐metabolic landscape in the tumour microenvironment, and whether glycans can synergize with immunotherapy as a way of rewiring T‐cell effector functions against cancer cells. [ABSTRACT FROM AUTHOR]