Deciphering the role of glycolipids as emerging therapeutic targets in EMT-driven cancer progression

Abstract Epithelial-to-mesenchymal transition (EMT) is a complex and dynamic cellular process during which epithelial cells lose their polarity and cell adhesion capabilities and subsequently express mesenchymal stem cell-like phenotype, including increased invasiveness, migration, resistance to programmed cell death, and synthesis of extracellular matrix components. Although several studies to date have demonstrated the intricate signalling pathways and important transcriptional regulators that drive EMT, glycolipids are now emerging as a significant modulator of the EMT transition. Alterations in glycolipid composition activate various growth factor signalling networks, which ultimately promote EMT and facilitate tumor development and metastasis. Despite this, there are still big gaps in our understanding of how glycolipid remodelling changes through time and space in the process of EMT and how these changes impact on the tumor microenvironment. Enzyme inhibitors, monoclonal antibodies, glycolipid-based vaccines, synthetic analogues, CRISPR–Cas9, and CAR-T cell therapies are some of the therapeutic strategies under study that have the potential to disrupt the glycolipid-driven EMT-signalling cascade and hinder tumor progression. Collectively, these therapeutic treatments have emerged as intriguing candidates for inhibiting glycolipid-driven EMT signalling and slowing metastatic invasion. The modified expression profiles of glycolipids may serve as valuable biomarkers for the molecular status of EMT and metastatic potential. Capturing these expression patterns may enable patient stratification, early diagnosis, and the identification of novel therapeutic targets. This review aims on recent progress in the use of glycolipid modulation of EMT. Potential therapeutic implications are also discussed here, to bring a new dimension to the cancer therapy.