Spermine Synthase Engages in Macrophages M2 polarization to Sabotage Antitumor Immunity in Hepatocellular Carcinoma

Abstract Disturbances in tumor cell metabolism reshape the tumor microenvironment (TME) and impair antitumor immunity, but the implicit mechanisms remain elusive. Here, we found that spermine synthase (SMS) was significantly upregulated in tumor cells, which correlated positively with immunosuppressive microenvironments and predicted poor survival in hepatocellular carcinoma (HCC) patients. Via “subcutaneous” and “orthotopic” HCC syngeneic mouse models and a series of in vitro coculture experiments, we identified elevated SMS level in HCC cells played a role in immune escape mainly through its metabolic product spermine, which induced tumor-associated macrophage (TAM) reprogramming and subsequently corresponded with a decreased antitumor functionality of CD8+ T cells. Mechanistically, we discovered that spermine reprogrammed TAM mainly by activating the PI3K-Akt-mTOR-S6K signaling pathway. Spermine inhibition in combination with immune checkpoint blockade effectively diminishes tumor burden in vivo. Our results expand the understanding of the critical role of metabolites in regulating cancer progression and anti-tumor immunity, and open new avenues for developing novel therapeutic strategies against HCC.