Targeting IL-17 family cytokines and receptors in hepatocellular carcinoma: From biology to combination immunotherapy

Immune checkpoint inhibitor (ICI)-based combinations have reshaped systemic therapy for unresectable hepatocellular carcinoma (HCC), yet durable responses remain limited, underscoring the need for mechanism-driven partners that reprogram the cirrhosis-conditioned tumor microenvironment. Here, we synthesize evidence supporting IL-17 family signaling as such a tractable axis and emphasize three translational takeaways. First, "IL-17 blockade" is not a single intervention: canonical IL-17A/F signaling through IL-17RA/RC differs from non-canonical nodes, including IL-17C signaling via IL-17RA/IL-17RE and the dual-ligand IL-17RB node (IL-25 versus IL-17B), which can yield context-dependent-and potentially opposing-effects. Second, HCC-focused models implicate an IL-17A-STAT3-PD-L1 immune-evasion circuit and show that IL-17A neutralization can enhance the activity of PD-1/PD-L1 blockade, positioning IL-17A/F inhibition primarily as an ICI-sensitizing strategy. Third, we argue that clinical translation should prioritize biomarker-guided, etiology-aware early-phase studies with on-treatment pharmacodynamic readouts, rather than unselected monotherapy, while explicitly accounting for infection and gut-barrier risks in cirrhosis.