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Life sciences · Journal article
Frontiers in Immunology · October 1, 2026
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Background Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related mortality worldwide. Despite the clinical success of immune checkpoint inhibitors, a substantial proportion of patients exhibit primary resistance, largely attributable to the immunosuppressive “cold” tumor microenvironment (TME). Saikosaponin D (SSd), a triterpenoid saponin derived from Bupleurum falcatum L., has emerged as a multifaceted immunomodulator with potential to remodel the TME, yet its role in converting “cold” HCC to an immunologically responsive “hot” phenotype remains systematically unexplored. Objective This review proposes a hypothesis-generating framework for saikosaponin D mediated cold-to-hot immune conversion in hepatocellular carcinoma. We synthesize preclinical evidence and integrate it into a dynamic temporal model to guide future research. Materials and methods We systematically searched PubMed, EMBASE, Web of Science, and Cochrane Library from January 2020 to December 2025. Search terms included saikosaponin D, hepatocellular carcinoma, and immunomodulation. The search was broadened to solid tumor immunology due to limited hepatocellular carcinoma specific studies. Two investigators screened and extracted data. From 306 initial records, 139 publications were included. Results Saikosaponin D modulates multiple signaling pathways including PI3K/AKT/mTOR, STAT3, HIF-1α, and TGF-β. It may promote immunogenic cell death, dendritic cell maturation, T-cell recruitment, macrophage repolarization, and metabolic remodeling. We propose a four-stage temporal model of immune conversion. Low oral bioavailability and missing orthotopic validation are key challenges that nanoformulation and organoid models may overcome. Conclusions Saikosaponin D shows multi-target immunomodulatory potential as a microenvironment-priming agent. The current evidence is largely indirect and derived from non-hepatocellular carcinoma models. Future validation requires orthotopic studies, advanced nanoformulations, and formal synergy testing. This framework offers testable hypotheses rather than therapeutic claims.