This dataset contains a 4D-DIA proteomic analysis of B16F10 mouse melanoma cells treated with SMT (SM@CMC-KP101). B16F10 cells were divided into two groups: a PBS control group and an SMT treatment group. After drug exposure, cellular proteins were extracted, digested and analyzed by LC-MS/MS using a Q Exactive HF mass spectrometer. The aim of this study is to identify differentially expressed proteins and perturbed pathways associated with the cytotoxic and anti-tumor effects of SMT on melanoma cells, providing insights into its molecular mechanisms of tumor cell killing.