RIPK3 Orchestrates Fatty Acid Metabolism in Tumor-Associated Macrophages and Hepatocarcinogenesis

TLDR

Metabolic reprogramming of tumor‑associated macrophages (TAMs) is essential for their polarization and for hepatocarcinogenesis, yet the mechanisms driving this reprogramming remain unclear. RIPK3 deficiency in TAMs reduces reactive oxygen species, blocks caspase‑1–mediated PPAR cleavage, activates PPAR, enhances fatty‑acid oxidation, and drives M2 polarization within the tumor microenvironment. Loss of RIPK3 in HCC‑associated macrophages promotes M2 TAM accumulation and tumorigenesis, while RIPK3 restoration or fatty‑acid oxidation inhibition reverses immunosuppression and suppresses HCC growth, underscoring RIPK3‑mediated lipid reprogramming as a therapeutic target.

Abstract

Metabolic reprogramming is critical for the polarization and function of tumor-associated macrophages (TAM) and hepatocarcinogenesis, but how this reprogramming occurs is unknown. Here, we showed that receptor-interacting protein kinase 3 (RIPK3), a central factor in necroptosis, is downregulated in hepatocellular carcinoma (HCC)-associated macrophages, which correlated with tumorigenesis and enhanced the accumulation and polarization of M2 TAMs. Mechanistically, RIPK3 deficiency in TAMs reduced reactive oxygen species and significantly inhibited caspase1-mediated cleavage of PPAR. These effects enabled PPAR activation and facilitated fatty acid metabolism, including fatty acid oxidation (FAO), and induced M2 polarization in the tumor microenvironment. RIPK3 upregulation or FAO blockade reversed the immunosuppressive activity of TAMs and dampened HCC tumorigenesis. Our findings provide molecular basis for the regulation of RIPK3-mediated, lipid metabolic reprogramming of TAMs, thus highlighting a potential strategy for targeting the immunometabolism of HCC.