Tumor-associated macrophages (TAMs) are pivotal drivers of hepatocellular carcinoma (HCC) progression, and blocking TAM M2 polarization has the potential to dampen tumor microenvironment remodeling. In this study, we screened a series of phenylethanoid and phenylpropanoid glycosides and identified syringin as a natural compound capable of inhibiting M2 polarization while promoting M1 polarization in macrophages. Single-cell RNA sequencing confirmed that syringin reduced TAM M2 polarization and significantly impaired tumor microenvironment remodeling. In detail, syringin indirectly reduced the stability of MYC proto-oncogene protein (MYC), which is required for driving a broad set of targets, including Arg1, Il10, Ym1, Mrc1, and Cd274. Using affinity-based protein profiling (ABPP), we revealed dihydrolipoamide S-acetyltransferase (DLAT) as a direct target of syringin. DLAT possesses protein acetyltransferase activity that acetylates MYC at K148. Syringin bound DLAT at residues R430 and N576 and disrupted the DLAT/MYC axis, thereby blocking MYC acetylation and promoting the ubiquitination and degradation of MYC protein. Additionally, syringin enhanced the efficacy of programmed cell death protein 1 blockade in mouse and patient-derived xenograft models, offering a potential adjunctive agent for HCC.

Hepatocellular carcinoma (HCC)  /  Tumor-associated macrophages (TAMs)  /  Macrophage polarization  /  Dihydrolipoamide S-acetyltransferase (DLAT)  /  MYC degradation  /  Syringin  /  Single-cell RNA sequencing (scRNA-seq)  /  Tumor microenvironment (TME)