Sialic Acids: Sweet modulators fueling cancer cells and domesticating the tumor microenvironment

Abstract

Tumor microenvironment (TME) can shift towards either immune activation or immunosuppression, influenced by various factors. Recent studies have underscored the pivotal role of sialic acids, a group of monosaccharides with a 9-carbon backbone, in modulating the TME. Aberrant expression or abnormal addition of sialic acids to the surface of cancer cells and within the tumor stroma has been identified as a key contributor to tumor progression. Abnormal sialylation on cancer cell surfaces can inhibit apoptosis, enhance cell proliferation, and facilitate metastasis. Notably, recent findings suggest that dysregulated sialic acid expression in the TME actively contributes to shaping an immunosuppressive niche by reducing the population of anti-tumor immune cells and impairing immune cell function. The mechanisms by which sialic acids foster immune escape and shape the immunosuppressive TME have been partially unraveled, particularly through interactions with sialic acid receptors on immune cells. Importantly, several sialic acid-targeted therapies are currently advancing into clinical trials, offering promising prospects for clinical translation. This dysregulated sialylation represents a significant opportunity for molecular diagnostics and therapeutic interventions in oncology. Targeting aberrant sialylation or disrupting the interaction between sialic acids and their receptors offers potential strategies to reprogram the TME towards an anti-tumor phenotype, thereby facilitating the advancement of innovative cancer therapies.

Keywords: Glycosylation; Immune evasion; Sialic acid; Siglec; Tumor microenvironment.