Rewiring the tumor microenvironment in hepatocellular carcinoma: mechanism-driven integration of immunotherapy and locoregional strategies

Hepatocellular carcinoma (HCC) arises in a cirrhotic, tolerogenic liver and within a heterogeneous tumor microenvironment (TME) that constrains the efficacy of single-agent systemic therapy. Although immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs have enhanced results, clinicians still lack a mechanistic framework to match specific combinations and locoregional therapies to distinct TME states or disease stages. Here, we synthesize late-phase clinical trial data and experimental studies to link three dominant TME phenotypes - inflamed, immune excluded and immune desert - to first-line ICI-based regimens, including atezolizumab-bevacizumab, durvalumab-tremelimumab, nivolumab-ipilimumab and tyrosine kinase inhibitor-ICI combinations. We outline how the vascular endothelial growth factor (VEGF)-immunity axis, immunogenic cell death after transarterial chemoembolization (TACE), ablation and radiotherapy, and cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING)-driven type I interferon signaling jointly rewire the TME and underpin the emerging “TACE-plus” standard (TACE + ICI + anti-VEGF therapy) in selected intermediate-stage HCC. We then integrate high response-rate regimens into practical algorithms for conversion and neoadjuvant therapy, cirrhosis-specific toxicity management and post-progression sequencing after ICI- or TACE-based treatment. Finally, we map next-generation approaches - Glypican-3-directed chimeric antigen receptor T-cell (CAR-T)/natural killer (NK)/tumor-infiltrating lymphocyte (TIL) products, novel checkpoints such as T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), STING agonists, and personalized neoantigen vaccines - onto putative TME states. We further highlight biomarker priorities, including β-catenin-mediated immune exclusion, angiogenic and interferon signatures, circulating tumor DNA and epigenetic readouts, and the gut-liver axis. A TME-anchored view of HCC provides a rational basis for integrating systemic and locoregional therapies, expanding curative opportunities and designing phenotype-enriched trials.