The sialic acid-Siglec immune checkpoint: an opportunity to enhance immune responses and therapy effectiveness in melanoma

Modulation of immune responses through immune checkpoint blockade has revolutionized cutaneous melanoma treatment. However, it is still the case that not all patients respond successfully to these therapies, indicating the presence of as yet unknown resistance mechanisms. Hence, it is crucial to find novel targets to improve therapy efficacy. One of the described resistance mechanisms is regulated by immune inhibitory Siglec receptors, which are engaged by the carbohydrates sialic acids expressed on tumour cells, contributing to programmed cell death protein-1 (PD1)-like immune suppression mechanisms. In this review, we provide an overview on the regulation of sialic acid synthesis, its expression in melanoma, and the contribution of the sialic acid-Siglec axis to tumour development and immune suppressive mechanisms in the tumour microenvironment. Finally, we highlight potential sialic acid-Siglec axis-related therapeutics to improve the treatment of melanoma. Melanoma cells have a high expression of sialic acids, which bind inhibitory receptors on immune cells called Siglecs, leading to immune evasion. Hence, the sialic acid-Siglec axis is a novel immune checkpoint to be targeted for the treatment of melanoma.