The Evolving Landscape of Hepatocellular Carcinoma Therapy: From Conventional Modalities to TME-Responsive Prodrug Design Strategies.

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, remains a major cause of cancer-related mortality. Despite advances in resection, transplantation, locoregional therapy, and systemic treatment, recurrence, resistance, toxicity, tumor heterogeneity, and impaired hepatic reserve limit durable benefit. Features of the HCC tumor microenvironment (TME) may serve as conditional activation signals for prodrug design. A prodrug is a pharmacologically inactive or less active derivative that undergoes chemical or enzymatic conversion after administration to generate or release an active drug. This review links the limitations of HCC treatments to prodrug-design requirements and evaluates bona fide prodrugs activated by acidity, redox imbalance, hypoxia, disease-associated enzymes, or lactate-coupled processes. Responsive carriers containing unmodified active drugs, imaging probes, and nanodelivery systems without a prodrug component are considered separately. Unlike previous reviews centered on broad stimuli-responsive nanomedicine or individual TME cues, this review uses a clinically anchored framework to assess whether proposed activation signals discriminate HCC from adjacent inflamed, fibrotic, or cirrhotic liver. It further integrates interpatient and intratumoral heterogeneity, off-target activation, impaired hepatic function, and the maturity of the evidence into the assessment of selectivity and translational feasibility. Because most HCC-directed systems remain supported by cellular or animal studies, improved selectivity, reversal of resistance, reduced toxicity, and survival benefit cannot yet be assumed. Future development should prioritize quantitative biomarker-guided activation, multi-input designs, spatial pharmacokinetic/pharmacodynamic assessment in disease-relevant models, and mechanism-based combinations that remain manufacturable. These advances may enable more controlled intratumoral drug exposure, but clinical value remains to be established.