Targeting SAMD1 enhances the effect of anti-PD-1 plus lenvatinib therapy in hepatocellular carcinoma by increasing ferroptosis sensitivity and immune response.

[BACKGROUND] Combination therapy of anti-PD-1 plus lenvatinib has shown effective anti-tumour effects for unresectable hepatocellular carcinoma (HCC), but the overall prognosis of HCC is still unsatisfactory. Elucidating the molecular mechanism underlying HCC progression contributes to develop new effective treatment in order to enhances the response of anti-PD-1 plus lenvatinib therapy and improve the patients prognosis.

[METHOD AND RESULTS] Here, we reported that targeting SAMD1 in HCC cells via small interference RNA-containing ZIF-90@HA (ATP/acid-responsive) Nanoparticles (ZIF-90@siRNA@HA NPs, ZSH NPs) significantly enhanced the anti-tumour effects of anti-PD-1 plus lenvatinib in vivo. Targeting SAMD1 in HCC cells not only increased cellular ROS abundance by inhibiting glycolysis and enhancing oxidative phosphorylation (OXPHOS) to increase ferroptosis sensitivity, but also inhibited the expression of CCL28, thereby reducing the recruitment of Treg cells, and improving the immunosuppression of tumour microenvironment. Mechanistically, SAMD1 suppression inhibits the expression of NUAK2 via Hippo pathway, thereby decreasing the phosphorylation of PFKP Ser386 and promoting the ubiquitination degradation of PFKP in HCC. Further study demonstrated that SAMD1 inhibition increased the expression of ITIH5 by regulating H3K4me3 demethylation at the ITIH5 promoter and then regulates Hippo pathway.

[CONCLUSIONS] Our study revealed the potential application of targeting SAMD1 in HCC treatment by enhancing ferroptosis sensitivity and immune response.