Intercepting hepatocellular carcinoma in chronic hepatitis B: a structured critical review of Chinese herbal medicine and the immune–fibrotic evidence

Patients with chronic hepatitis B (CHB) and advanced fibrosis or compensated cirrhosis remain at risk of incident hepatocellular carcinoma (HCC) despite antiviral therapy, creating a clinically relevant window for cancer interception. Chinese herbal medicine (CHM) combined with nucleos(t)ide analogs has been associated with fibrosis improvement and, in selected longitudinal studies, lower HCC incidence. This structured critical review asks whether CHM can intercept HCC by modifying actionable immune–fibrotic processes before tumor formation. We evaluated disease-side and CHM intervention evidence across macrophages/monocytes, T cells, natural killer cells, neutrophils, B cells, dendritic cells and myeloid-derived suppressor cells. Evidence maturity was assessed using pathological relevance, HCC linkage and temporal alignment, evidence level, sampling-compartment directness, functional validation and, for CHM evidence, translational potential. Specific CHM–immune-mechanism pairs were then mapped onto a four-tier interception framework. The T helper 17/regulatory T-cell axis (Th17/Treg) showed the clearest longitudinal human connection between fibrosis-associated immune imbalance and subsequent HCC. Macrophage and natural killer-cell programs were supported by cell-resolved fibrosis mechanisms, treatment-responsive changes and cross-stage HCC associations, whereas neutrophil evidence linked neutrophil extracellular traps with a less specific longitudinal neutrophil-to-lymphocyte-ratio signal. Evidence for B cells, dendritic cells and myeloid-derived suppressor cells was less continuous across disease stages. On the intervention side, epigallocatechin-3-gallate–HMGB1 (high-mobility group box 1)/NLRP3 (NLR family pyrin domain-containing 3) and matrine–NKG2D (natural killer group 2 member D) provided mechanistic evidence, while Fuzheng Huayu–macrophage NLRP3–hepatic stellate cell, Biejia-Ruangan–Th17/Treg and Fuzheng Huayu–lymphocyte–hepatic stellate cell combinations converged with formulation-level signals of reduced HCC incidence. However, no longitudinal cohort has linked defined CHM exposure, cell-resolved immune change, fibrosis trajectory and lower incident HCC risk within one time-ordered pathway. We therefore propose a minimum clinical–experimental design to test whether CHM-induced immune changes contribute to lower incident HCC risk.