From anatomical to biological resectability: navigating adaptive resistance in hepatocellular carcinoma conversion

The advent of conversion therapy for hepatocellular carcinoma (HCC) marks a critical transition from palliative care to curative-intent surgery. While clinical success rates are rising, the molecular determinants of sustained remission remain inadequately defined. We propose that effective downstaging may indicate a comprehensive modulation of the tumor immune microenvironment potentially transitioning it from an immune-excluded to an inflamed phenotype based on early translational correlative data. However, the aggressive therapeutic selective pressure of targeted, immune, and locoregional therapies paradoxically fuels clonal evolution. In specific contexts, this therapeutic stress is hypothesized to drive treatment-resistant subclones through mechanisms such as Wnt/β-catenin signaling and metabolic adaptation. To navigate this therapeutic barrier, we advocate shifting the clinical objective from anatomical to biological resectability, operationally defined by a provisional set of measurable criteria including ctDNA clearance, robust CD8+ T-cell infiltration, and tertiary lymphoid structure maturation. By implementing a multidimensional surveillance framework that leverages liquid biopsies and AI-radiomics to track subclonal dynamics and minimal residual disease, clinicians can guide precise surgical interventions and intercept resistance, making a curative horizon attainable.