C-C motif glycoprotein ligand 5 (CCL5) and its GPCR CCR5: Macromolecular game-changers in cancer biology.

The C-C motif chemokine ligand 5 (CCL5; also known as RANTES) and its primary G-protein-coupled receptor (GPCR), CCR5, establish complicated signaling pathways, affecting tumor progression through context-dependent immunomodulation and direct contacts with neoplastic cells. This review summarizes current structural and functional evidence linking CCL5's O-linked glycosylation, oligomerization, and glycosaminoglycan interactions to its affinity for CCR5, tissue retention, and gradient formation-molecular attributes that govern leukocyte recruitment, stromal remodeling, angiogenesis, and metastasis. It also discusses mechanistic data showing how CCL5/CCR5 signaling promotes protumorigenic processes, including the recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), polarization of tumor-associated macrophages (TAMs), epithelial-mesenchymal transition (EMT), stabilization of programmed cell death-ligand 1 (PD-L1), and therapeutic resistance. In particular, in immune-activating conditions, the recruitment of conventional type 1 dendritic cells (cDC1s), natural killer (NK) cells, and CD8 T cells is augmented, hence fortifying anticancer immunity. Data from several tumors reveal both detrimental and beneficial effects, dependent on the tumor microenvironment (TME) and therapeutic context. Translational techniques employing CCR5 antagonists such as Maraviroc, GAG-binding modulators, glycoengineered CCL5 variants, delivery systems, and their integration with immune checkpoint inhibitors (ICIs) and targeted therapies are highlighted for their considerable therapeutic promise. Critical research priorities, encompassing single-cell phenotyping, CRISPR-mediated screening of chemokine pathways, and structural-functional mapping, are outlined to facilitate precise modulation of the CCL5/CCR5 axis in targeted cancer therapy. This review addresses structural biology and tumor immunology to identify the CCL5/CCR5 axis as a multifaceted yet promising biological target for innovative cancer therapeutics.