The joint anti-hepatocellular carcinoma mechanism of selenium and lenvatinib mediated by Nrf2-ferroptosis axis in M2 tumor associated macrophage

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited treatment options. Lenvatinib demonstrates efficacy but is associated with significant toxicity at standard doses. Tumor-associated macrophages (TAMs), especially the pro-tumor M2 phenotype, contribute to an immunosuppressive microenvironment in HCC by promoting immune evasion. Selenium (Se), an essential trace element with anticancer properties, can reduce M2-TAM infiltration; however, its potential synergy with low-dose lenvatinib (L-Len) to enhance antitumor efficacy while minimizing toxicity remains unexplored. METHODS: Subcutaneous HCC models were established to assess the therapeutic effects of Se combined with L-Len. Tumor growth, toxicity, and infiltration of M2-TAMs were evaluated. Mechanistic studies analyzed Nrf2 activation and downstream targets (GPx4/xCT) in TAMs to determine ferroptosis-inducing effects of combined treatment. RESULTS: Se + L-Len showed comparable antitumor efficacy to standard-dose lenvatinib but with reduced toxicity. The combination reduced M2-TAMs infiltration and induced ferroptosis by suppressing Nrf2 and GPx4/xCT. CONCLUSION: Se enhances L-Len's efficacy, and a key mechanism contributing to this synergy appears to be the targeting of Nrf2-mediated ferroptosis in M2-TAMs. This suggests a potential strategy to improve HCC treatment while minimizing toxicity, which warrants further investigation in more clinically relevant models.