Chemodynamic therapy (CDT) is a highly targeted approach to treat cancer since it converts hydrogen peroxide into harmful hydroxyl radicals (OH & BULL;) through Fenton or Fenton-like reactions. However, the systemic toxicity of metal-based CDT agents has limited their clinical applications. Herein, a metal-free CDT agent: 2,4,6-tri(4-pyridyl)-1,3,5-triazine (TPT)/ [closo-B12H12]2-(TPT@ B12H12) is reported. Compared to the traditional metal-based CDT agents, TPT@B12H12 is free of metal avoiding cumulative toxicity during long-term therapy. Density functional theory (DFT) calculation revealed that TPT@B12H12 decreased the activation barrier more than 3.5 times being a more effective catalyst than the Fe2+ ion (the Fenton reaction), which decreases the barrier about twice. Mechanismly, the theory calculation indicated that both [B12H12]-& BULL; and [TPT-H]2+ have the capacity to decompose hydrogen into 1O2, OH & BULL;, and O2-& BULL;. With electron paramagnetic resonance and fluorescent probes, it is confirmed that TPT@B12H12 increases the levels of 1O2, OH & BULL;, and O2-& BULL;. More importantly, TPT@B12H12 effectively suppress the melanoma growth both in vitro and in vivo through 1O2, OH & BULL;, and O2-& BULL; generation. This study specifically highlights the great clinical translational potential of TPT@B12H12 as a CDT reagent. 2,4,6-Tri(4-pyridyl)-1,3,5-triazine (TPT)/ [closo-B12H12]2-(TPT@B12H12), a metal-free chemodynamic therapy (CDT) agent, decreases the activation barrier more than 3.5 times being a more effective catalyst than the Fe2+ ion (the Fenton reaction), which decreases the barrier about twice. More importantly, TPT@B12H12 effectively suppress the melanoma growth both in vitro and in vivo through 1O2, OH & BULL;, and O2-& BULL; generation. image