Editor's Note: Hepatocellular carcinoma (HCC) is a common and highly lethal malignancy, with its treatment methods continuously evolving. In recent years, immunotherapy has become a hotspot in liver cancer treatment. Recently, Professor Zhexiong Lian's team from Southern Medical University published a paper in the Journal of Hepatology, revealing the potential value of inhibiting OXCT1 activity in tumor-associated macrophages (TAMs) for treating HCC. The study found that high OXCT1 expression is closely associated with poor prognosis in HCC patients. By inhibiting OXCT1, TAMs can be reprogrammed to an anti-tumor phenotype, enhancing the cytotoxicity of CD8+ T cells, thereby providing a new strategy for immunotherapy of liver cancer.

Research Background

The liver is a major ketogenic organ, where ketones are primarily metabolized in peripheral tissues through the key enzyme OXCT1. Previous research by the team found that HCC cells re-activate ketolysis via OXCT1 expression, promoting tumor progression. However, whether OXCT1 regulates anti-tumor immunity remains unclear.

Research Methods

To investigate the expression pattern of OXCT1 in vivo in HCC, researchers conducted multiplex immunohistochemistry (mIHC) on human HCC specimens. To explore the role of OXCT1 in mouse liver cancer TAMs, researchers bred LysMcreOXCT1f/f mice (conditional knockout of OXCT1 in macrophages).

Research Results

Researchers found that inhibiting OXCT1 expression in TAMs through the succinate-H3K4me3-Arg1 pathway alleviated CD8+ T cell exhaustion.

Initially, they observed high OXCT1 expression in steady-state liver macrophages, with further increased expression in TAMs. Lack of OXCT1 in macrophages reprogrammed TAMs to an anti-tumor phenotype, inhibited tumor growth, reduced CD8+ T cell exhaustion, and enhanced CD8+ T cell cytotoxicity, thus suppressing tumor growth.

Mechanistically, high OXCT1 expression induced the accumulation of the ketolytic byproduct succinate in TAMs, promoting Arg1 transcription by increasing H3K4 trimethylation (H3K4me3) levels on the Arg1 promoter. Moreover, the OXCT1 inhibitor pimozide suppressed Arg1 expression and TAM polarization towards a pro-tumor phenotype, reducing CD8+ T cell exhaustion and slowing tumor growth. The study also elucidated a positive correlation between high OXCT1 expression in macrophages and poor prognosis in HCC patients.

Research Conclusions

The results indicate that OXCT1 inhibits anti-tumor immunity through epigenetic mechanisms, suggesting that inhibiting OXCT1 activity in TAMs is an effective method for treating liver cancer.

Research Significance

The complex metabolism of liver macrophages plays a crucial role in HCC progression and immune regulation. Targeting macrophage metabolism to counteract immune suppression opens a promising avenue for HCC treatment. The study found that the ketogenic gene OXCT1 is highly expressed in TAMs and promotes tumor growth by reprogramming TAMs to a pro-tumor phenotype. Furthermore, strategic drug intervention or genetic downregulation of OXCT1 in TAMs can enhance anti-tumor immunity and slow tumor growth. The findings suggest that inhibiting OXCT1 activity in TAMs is an effective method for treating liver cancer.

Original Article Link: Zhu CX, Yan K, Lian ZX, et al. Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma. Journal of Hepatology. (2024)