Table 2_From cold to hot: the immunomodulatory framework of Saikosaponin D in hepatocellular carcinoma therapy.docx

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.</p>Objective<p>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.</p>Materials and methods<p>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.