Chemodynamic therapy (CDT) is a highly targeted approach to treat cancer since it converts hydrogen peroxide into harmful hydroxyl radicals (•OH) through Fenton or Fenton-like reactions in tumor microenvironments. However, the systemic toxicity of metal-based CDT agents has limited their clinical use due to harmful side effects and low efficiency. Herein, we generate a novel CDT agent: 2,4,6-tri(4-pyridyl)-1,3,5-triazine (TPT)/ [closo-B12H12]2−(TPT@ B12H12), which is metal-free and may avoid cumulative toxicity during long-term therapy. We investigated the Fenton-like catalytic activity and anti-melanoma effects of the synthesized boron cluster supramolecular framework TPT@B12H12, and the results showed that it could effectively suppress the melanoma growth both in vitro and in vivo through ROS generation. The favorable properties of the TPT@B12H12 system were rationalized by means of quantum chemistry DFT calculations revealing that TPT@B12H12 substantially decreases the activation barrier compared to the effective Fe2+ ion commonly used in Fenton reactions. This study highlights the great clinical translational potential of TPT@B12H12 as a CDT agent, potentially serving as a prelude to the rapid development of metal-free CDT agents.