Immunometabolic heterogeneity in hepatocellular carcinoma: Transforming cold tumors into hot tumors

Abstract

Despite significant progress in the field of immunotherapy for hepatocellular carcinoma (HCC), many patients still fail to respond to the treatment and develop "cold tumors". This review systematically clarifies the immunological and metabolic heterogeneity between “cold” and “hot” tumors in HCC—cold tumors are characterized by immunosuppression and more disordered metabolism, while hot tumors exhibit robust immune cell infiltration and active metabolism and respond favorably to immune checkpoint inhibitor therapy. We also summarize the biomarkers of HCC cold tumors and the therapeutic strategies for converting cold tumors to hot tumors, including cryoablation, immune combination therapy, nanocarrier-based approaches, vaccines, and metabolic interventions. Moreover, establishment of a hierarchical evidence system to evaluate these strategies revealed that immune combination therapy has sufficient clinical validation and significant clinical value, whereas other therapies require further research. We hope that this review will help improve the understanding of cold and hot HCC tumors and provide a novel perspective for the precision treatment of HCC.