Limited stability of metal nanoparticles hinders their long-term uses and applications. For metal nanoclusters, this is even more critical as physicochemical properties rely on the structure of only a few hundred atoms. Here, we study the irreversible change that Au25(SR)18 suffers upon interaction with 2D metal surfaces. Experimental and DFT results allow us to identify the triggering factors of the decomposition process. Our thermodynamic-based approach can be extended to other metal nanocluster/substrates, turning it into a useful tool for predicting the nanoscale stability of these systems.