Atypical Chemokine Receptor CCRL2 Shapes Tumor Spheroid Structure and Immune Signaling in Melanoma.

C-C motif chemokine receptor-like 2 (CCRL2) is an atypical chemokine receptor (ACKR) that binds chemerin with high affinity but lacks classical G protein-coupled signaling. Instead, it functions as a non-signaling presenter of chemerin to CMKLR1-expressing cells, modulating antitumor immunity. CCRL2 is highly expressed in the tumor microenvironment and various human cancers, and its expression has been linked to delayed tumor growth in mouse models, primarily through the chemerin/CMKLR1 axis. While CCRL2's role in immune surveillance is well established, its tumor cell-intrinsic functions remain less clear. Here, we investigated the impact of CCRL2 overexpression and knockout on tumor cell behavior in vitro. Although CCRL2 did not affect proliferation, migration, or clonogenicity in B16F0 melanoma and LLC cells, it significantly influenced spheroid morphology in B16F0 cells. Transcriptomic analysis revealed that CCRL2 modulates innate immune signaling pathways, including TLR4 and IFN-γ/STAT1, with context-dependent downstream effects. These findings suggest that CCRL2 shapes tumor architecture by rewiring inflammatory signaling networks in a cell-intrinsic manner. Further studies in other cancer types and cell models are needed to determine whether CCRL2's regulatory role is broadly conserved and to explore its potential as a therapeutic target in solid tumors.