CXC chemokines as context-dependent regulators of immunity, homeostasis and cancer

Chemokines are a large family of small secreted proteins that mainly orchestrate immune cell trafficking and tissue organization. Among them, the CXC chemokine family plays a central role in regulating immune surveillance, inflammation, angiogenesis and stem cell dynamics. Despite their relatively simple conserved fold - characterized by a β-sheet core and a C-terminal α-helix - CXC chemokines exhibit remarkable functional diversity. This diversity arises from structural plasticity, including concentration-dependent monomer-dimer equilibria and interactions with glycosaminoglycans (GAGs), which collectively shape chemokine gradients, protect against proteolytic degradation and fine-tune receptor activation and selectivity. Emerging evidence indicates that these structural and spatial determinants enable CXC chemokines to regulate not only leukocyte recruitment but also tissue homeostasis, haematopoietic stem cell quiescence, activation, and microenvironmental organization. Dysregulation of CXC chemokine signalling contributes to a broad spectrum of human diseases, including chronic inflammatory disorders, degenerative conditions and cancer, where altered gradient formation and receptor engagement reprogram tumour immunity and promote metastatic progression. Here, we examine the structural principles governing CXC chemokine function, discuss how monomer-dimer dynamics and coordinated interactions regulate signalling specificity, and explore how context-dependent chemokine activity shapes immunity in health and disease.