Transmembrane lectins in cancer immunity: emerging drivers of myeloid-mediated immunosuppression

Abstract

Immune evasion in cancer is sustained by coordinated interactions between malignant, stromal, and immune cells within the tumor microenvironment. Among these, myeloid populations are major regulators of immunosuppression, but the diverse signals that shape their functional states remain insufficiently integrated within current conceptual frameworks. Altered glycosylation is a recurrent feature of cancer that reshapes the ligands available to lectin receptors. Within this landscape, transmembrane lectins expressed by myeloid cells occupy a distinctive mechanistic position, coupling extracellular glycan recognition to intracellular signaling programs that shape myeloid-cell function. In this review, we integrate evidence from tumor glycobiology, myeloid immunology, receptor signaling, experimental models, and therapeutic development to examine how C-type lectin receptors and Siglecs contribute to myeloid-mediated immune suppression. We discuss how these receptors influence macrophage and dendritic-cell states, antigen presentation, phagocytosis, cytokine production, metabolism, and immune-checkpoint regulation, while emphasizing the dependence of these outcomes on ligand context, receptor architecture, cellular identity, and tissue organization. We further consider how receptor redundancy, overlapping glycan specificities, and model-dependent effects complicate the interpretation and therapeutic targeting of lectin pathways. Finally, we discuss emerging approaches directed at lectin–glycan interactions and downstream signaling, together with their potential to complement established immunotherapies. By bringing together concepts that are often considered separately, this review positions transmembrane lectins as important integrators of the tumor glycan landscape and myeloid immune regulation, while defining key questions that must be addressed to translate glyco-immune mechanisms into effective cancer therapies.