This dataset contains two mass spectrometry-based proteomic experiments investigating the effects of indole-3-propionic acid on hepatocellular carcinoma and macrophage lipid metabolism. The first experiment includes liver tumor tissues from orthotopic hepatocellular carcinoma-bearing mice treated with lenvatinib plus anti-PD-1 therapy with or without indole-3-propionic acid supplementation. The second experiment includes mouse bone marrow-derived macrophages treated with or without indole-3-propionic acid in vitro. These analyses were performed to identify IPA-associated changes in protein expression and signaling pathways related to lipid droplet metabolism, lipophagy, autophagy, macrophage polarization, and antitumor immune responses. The deposited files include raw mass spectrometry data, protein and peptide identification results, quantitative expression matrices, experimental metadata, and data-processing outputs.