p-FADD-CD8+T cell axis determines hepatocellular carcinoma response to immune checkpoint inhibitors

The heterogenicity of hepatocellular carcinoma (HCC) remains a key obstacle in turning the majority of ‘immune-cold’ tumors ‘hot’ for effective immune checkpoint inhibitors (ICIs). Through analyzing the naturally-existed ‘hot’ HCC variants, we identified fas-associated death domain (FADD) as a key molecule upregulated in patients with dense tumor-filtrating CD8+T cells and better response to ICIs. Apart from the canonical role in apoptosis pathway, our data showed that CRISPR knockout of hepatoma-intrinsic Fadd led to increased tumor weights in immunocompetent but not immunodeficient mice, accompanied with decreased numbers and IFN-γ/TNF-ɑ production of tumor-filtrating CD8+T cells. Mechanistically, phosphorylated FADD translocated into cell nucleus, where it interacted with Sam68 to upregulate NF-κB transcription of CCL5, thereby promoted CD8+T cell tumor infiltration. Interestingly, anti-PD1 triggered FADD phosphorylation by CD8+T cell-derived IFN-γ/TNF-ɑ in ICI-sensitive, but not resistant tumors. Sequential FADD activation through genetic or pharmacologic approaches to orchestrate p-FADD-CD8+T cell axis therefore overcame ICI resistance in ICI-resistant orthotopic and spontaneous HCC mouse models in vivo. Taken together, our findings may provide insights into the combinatory immunotherapy approaches for the majority of HCC patients in the future.