Proteoglycans as Regulators of Receptor Trafficking and Spatial Signaling in Cancer

Cellular responses depend on the coordinated regulation of receptor activation, trafficking, and signaling across distinct membrane and intracellular compartments. Proteoglycans (PGs), traditionally regarded as structural components of the extracellular matrix and co-receptors, are now emerging as active organizers of receptor dynamics. This review examines the mechanisms through which PGs regulate receptor trafficking and spatial signaling in cancer. Recent studies addressing the roles of proteoglycans in receptor clustering, endocytic pathway selection, intracellular trafficking, recycling, lysosomal degradation, endosomal signaling, exosome biogenesis, and nuclear receptor transport were evaluated, with particular attention to the strength of direct evidence for trafficking. Particular attention was given to the complementary functions of proteoglycan core proteins, glycosaminoglycan chains, and extracellular matrix remodeling in shaping receptor behavior. Current evidence demonstrates that proteoglycans govern multiple stages of receptor biology by controlling ligand presentation, receptor accessibility, membrane organization, intracellular trafficking, and signaling persistence. Individual proteoglycans exert distinct effects on receptor fate, ranging from receptor downregulation and degradation to sustained endosomal signaling and nuclear receptor translocation. Cancer-associated alterations in proteoglycan expression, glycosaminoglycan sulfation, heparanase activity, ectodomain shedding, and glycocalyx organization remodel signaling networks, strengthen communication between tumor and stromal cells, and promote tumor progression, immune modulation, metastasis, and therapeutic resistance. Proteoglycans have emerged as fundamental regulators of receptor trafficking and signaling architecture. Through the integration of extracellular matrix organization with receptor dynamics, they shape the spatial and temporal properties of oncogenic signaling. This conceptual framework broadens our understanding of tumor biology and identifies proteoglycan-dependent regulation of receptor trafficking as a promising avenue for future therapeutic intervention.