Traditional Chinese medicine reverses immune checkpoint resistance through lactate metabolic reprogramming in hepatocellular carcinoma: Mechanisms and therapeutic implications.

ETHNOPHARMACOLOGICAL RELEVANCE: The compounds reviewed here originate from plants with long-standing use in East Asian traditional medicine. Epimedium brevicornu Maxim. (Yin Yang Huo), Scutellaria baicalensis Georgi (Huang Qin), Coptis chinensis Franch. (Huang Lian), and Curcuma longa L. (Jiang Huang) are documented in the Chinese pharmacopoeia for indications including liver insufficiency, heat-clearing, and abdominal masses-a traditional category encompassing hepatic tumours.

AIM OF THE STUDY: To examine how traditional Chinese medicine (TCM) bioactive compounds and classical formulations reprogram tumour lactate metabolism in hepatocellular carcinoma (HCC) and overcome immune checkpoint blockade (ICB) resistance, and to propose a translational framework.

MATERIALS AND

METHODS

Narrative review with structured literature search across PubMed, Web of Science, Embase, China National Knowledge Infrastructure, and ClinicalTrials.gov through March 2025. Studies reporting experimental or clinical evidence of TCM-mediated effects on glycolysis, lactate, or immune cell function in HCC were included; formal risk-of-bias grading was not performed, consistent with the narrative-review framing.

RESULTS

Elevated tumour lactate is associated with ICB resistance through T cell exhaustion, M2 macrophage polarisation, and PD-L1 stabilisation. TCM compounds-including baicalin (HIF-1α/CXCL9), berberine (AMPK), curcumin (HIF-1α/MCT4), and icaritin (JAK2/STAT3/PD-L1)-attenuate glycolysis and partially restore immune effector function in preclinical HCC. Selective MCT4 inhibition sensitises HCC to anti-PD-1 in immunocompetent models. Icaritin achieved Phase III validation (NCT03236636; HR = 0.40, p = 0.0046) in biomarker-enriched HCC.

CONCLUSIONS

TCM-mediated lactate metabolic reprogramming is a biologically plausible strategy warranting further investigation for ICB-resistant HCC. The current evidence linking lactate to ICB resistance in human HCC remains largely supportive and correlative rather than definitively causal-several pivotal mechanistic findings derive from non-HCC models-and should be interpreted accordingly. Biomarker-enriched, pharmacokinetically informed TCM-ICB combination trials with direct intratumoural lactate measurement are required.