Calceolarioside B targets MMP12 in the tumor microenvironment to inhibit M2 macrophage polarization and suppress hepatocellular carcinoma progression.

BACKGROUND

Tumor-associated macrophages (TAMs) are crucial in hepatocellular carcinoma (HCC) progression and prognosis, making them promising immunotherapy targets. In traditional Chinese medicine (TCM), qi stagnation and blood stasis are linked to the HCC tumor microenvironment (TME), but few studies explore the effects of related TCM herbs on the TME. Calceolarioside B, a key phenylethanoid glycoside in Akebiae Fructus, has not been well studied for its pharmacological activities or molecular targets, and its role in HCC remains unclear.

PURPOSE

This study aimed to investigate the effects of Calceolarioside B on TAMs in HCC and clarify its potential targets and regulatory mechanisms.

METHODS

Murine intrahepatic transplantation HCC models and macrophage-HCC cell co-culture systems were used to investigate the effects of Calceolarioside B on M2-like TAMs polarization and infiltration, and tumor growth. Cellular thermal shift assay, small molecular pull-down assay and surface plasmon resonance were utilized to identify the potential targets regulating M2-like TAMs. Single-cell RNA sequencing and TCGA dataset analyses clarified the differential expression, prognosis, and TAMs association of the potential targets in HCC.

RESULTS

Calceolarioside B reduces M2-like TAMs polarization and infiltration in the TME by binding to and inhibiting matrix metallopeptidase-12 (MMP12) form both macrophages and HCC cells, thereby preventing immunosuppressive effects. Public database analysis revealed that MMP12 overexpression promoted macrophage infiltration, with MMP12 macrophages preferentially aggregating in primary and metastatic HCC tumors.

CONCLUSION

Calceolarioside B is identified as a novel MMP12 inhibitor modulating TAMs in the TME, offering a potential TAM-targeting strategy for HCC therapy.