Spermidine synthase promotes liver cancer progression in a paracrine manner by altering the macrophage immunometabolic state

Purpose: Understanding the molecular mechanisms of adaptive regulation in the tumor microenvironment is crucial for precision therapy in hepatocellular carcinoma (HCC). We hypothesized that cargo proteins carried by extracellular vesicles (EVs) released in a hypoxic microenvironment might promote HCC progression by remodeling tumor-associated macrophages (TAMs).

Methods: EV protein analysis by label-free proteomics mass spectrometry of HCC cell lines of different tumor grades was performed. The promotional effect if spermidine synthase（SRM） on M2 polarized TAMs was further investigated using various biological approaches.

Results: SRM expression was positively correlated with liver cancer progression in HCC cell lines, liver cancer samples, and nude mouse models. In a mouse model, SRM expression was positively correlated with TAM infiltration and liver cancer progression. Pan-cancer dataset analysis confirmed that SRM overexpression in HCC tumors is correlated with poor patient prognosis. However, a hypoxic microenvironment is an internal driving factor for exosomal SRM that participates in microenvironmental modifications. Moreover, we defined a hitherto unknown pattern of microenvironmental crosstalk involving SRM in EVs, whereby macrophages complete the phenotypic fate of M2 tumor-associated macrophages through SRM uptake.

Conclusion: SRM regulation within the immune microenvironment is metabolically driven. By upregulating spermidine, which serves as a substrate for eIF5A hypusination, excessive oxidative phosphorylation (OXPHOS) assembly is achieved. This, in turn, leads to the expression of immunosuppressive marker molecules and ultimately promotes liver cancer progression. SRM, which is enriched in the EVs of HCC cells under hypoxic conditions, acts as a potent regulator linking polyamine and energy metabolism in TAMs, thereby promoting liver cancer progression.