Chemokine–receptor axes in immune–tumor cell communication: spatial niches, immune exclusion, and therapy resistance

Chemokine–receptor axes are traditionally viewed as leukocyte trafficking cues, but increasing evidence indicates that they also function as spatial and functional organizers of immune–tumor communication. In the tumor microenvironment, chemokine gradients determine which immune-cell subsets are recruited, where they are positioned, and whether they acquire antitumor or suppressive states. This review summarizes experimentally validated chemokine–receptor axes that shape spatial niches, immune exclusion, and therapy resistance in cancer. The CXCL12–CXCR4 axis serves as a prototype of stromal immune exclusion, particularly in pancreatic cancer, where CXCR4 blockade can improve immune accessibility but may require myeloid-directed combinations. CXCR2 ligand axes, including CXCL5–CXCR2 and IL-8/CXCR2 signaling, promote neutrophil-rich suppressive niches, CD8 + T-cell dysfunction, PD-L1 induction, and resistance to immune checkpoint blockade or chemotherapy. The CCL20–CCR6 axis recruits regulatory T cells and contributes to metastatic immune suppression, whereas CCL5–CCR5 signaling organizes perivascular macrophage niches and supports adaptive therapy resistance. CCL2-associated macrophage circuits further link monocyte recruitment, TAM polarization, and immunotherapy responsiveness. We discuss how single-cell and spatial technologies can validate these circuits and guide biomarker-driven therapies. Rather than targeting isolated ligand–receptor pairs, future strategies should reprogram chemokine-controlled immune ecosystems to overcome immune exclusion and treatment resistance.