Dietary supplementation of α-linolenic acid-rich flaxseed oil enhances anti-PD-1 protection against orthotopic hepatocellular carcinoma by reshaping gut homeostasis and improving anti-tumor immunity via gut-liver axis in mice

Blockade therapy of immune checkpoint with anti-programmed cell death (PD)-1 antibody has achieved tremendous success on the treatment of numerous malignant tumors, whereas there is still a problem of low response rate. In the present study, the complement of α-linolenic acid (ALA) on the impact of PD-1 immunotherapy for hepatocellular carcinoma (HCC) was investigated. We found that the ALA combined with PD-1 immunotherapy exerted superior in inhibiting tumor growth. Moreover, the combination treatment significantly changed diverse T cell subsets and ant-tumor immunity associated cytokine levels in plasma and tumor tissues. Intriguingly, gut dysbiosis was notably attenuated after the intervention by elevating the expression of intestinal tight junction proteins alonged with reducing liver lipopolysaccharide (LPS), as well as modulating gut microbiota and short-chain fatty acids (SCFAs). Collectively, these results indicated that the supplement with ALA strengthened anti-tumor immunity and reshaped the gut homeostasis to contribute to the PD-1 treatment against HCC.