The immune system safeguards as primary defense by recognizing nanomaterials and maintaining homeostasis, gaining a deeper understanding of these interactions may change the treating paradigm of immunotherapy. Here, we adopted copper as the principal component of nanoparticles (NPs), given its features of coordination with different benezenecarboxylate ligands to form metal-organic frameworks and complexes with distinct morphologies. As a result, four types of shape-tunable copper-coordinated NPs (CuCNPs) are developed: cuboctahedron, needle, octahedron, and plate NPs. Biocompatibility of CuCNPs varies across different cell lines (RAW264.7, THP-1, HEK 293 and HeLa) in a shape-dependent manner, with needle-shaped CuCNPs showing pronounced cytotoxicity (IC50:104.3 μg mL at 24 h). Among different shapes, a notable increase of 8.47% in the CD206 subpopulations is observed in needle-shaped CuCNPs, followed by 77% enhancement at 48 h. Overall, this study underscores the shape-dependent immune-regulatory effects of CuCNPs and sheds light on the rational design of nanoscale metal complexes for potential immunotherapy.