SOCS3 and hepatocellular carcinoma: Accordingly, mutations in genes involved in the INF-γ pathway, including loss of signaling-related genes (JAK 1/2) and amplification of suppressor genes, have been identified in patients that do not respond to anti-CTLA-4 and anti-PD-1 therapies, thereby reinforcing the suggested role of INF-γ signaling disruption in ICI resistance.46,47 Moreover, studies conducted on HCC tissues identified the presence of methylations in the suppressors of cytokine signaling genes SOCS-1 and SOCS-3, which are negative regulators of the JAK2-STAT signaling pathway.