Antibody-drug conjugates in treatment-resistant hepatocellular carcinoma: mechanistic insights, translational barriers, and a blueprint for salvage-line precision oncology.

Despite advances in immune checkpoint inhibitor (ICI)-based therapy, hepatocellular carcinoma (HCC) frequently develops treatment resistance, creating a need for mechanistically distinct therapies. Antibody-drug conjugates (ADCs) combine tumor-directed recognition with intracellular payload delivery, but their development in HCC is constrained by antigen heterogeneity, impaired macromolecular transport, and cirrhosis-associated pharmacokinetics. We propose that the salvage-line setting may represent a biomarker-defined niche rather than an intrinsically superior setting for ADCs. We introduce a Five-Layer Resistance Framework encompassing antigen-level resistance, cellular processing and trafficking, payload-specific resistance, tumor microenvironmental barriers, and systemic and liver-specific pharmacokinetic constraints. We further discuss liver-adapted engineering, combination strategies, toxicity, patient selection, and manufacturability. Integrating these elements may guide precision development of ADCs in treatment-resistant HCC while defining key translational gaps requiring prospective validation.