From cold to hot: the immunomodulatory framework of Saikosaponin D in hepatocellular carcinoma therapy
- 1College of Traditional Chinese Medicine, Hubei University of Chinese Medicine , ,
- 2College of Acupuncture-Moxibustion and Orthopedics, Hubei University of Chinese Medicine , ,
Abstract
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.
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BibTeX
@article{huang2026from,
title = {{From cold to hot: the immunomodulatory framework of Saikosaponin D in hepatocellular carcinoma therapy}},
author = {Xiaoyue Huang and Lin Liu and Meihui Qin and Runyue Liu},
journal = {Frontiers in immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1964907},
url = {https://europepmc.org/article/PMC/PMC13670170},
note = {CC BY},
}
RIS
TY - JOUR
TI - From cold to hot: the immunomodulatory framework of Saikosaponin D in hepatocellular carcinoma therapy
AU - Xiaoyue Huang
AU - Lin Liu
AU - Meihui Qin
AU - Runyue Liu
PY - 2026
DA - 2026/10/01
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1964907
UR - https://europepmc.org/article/PMC/PMC13670170
AB - 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.
SN - 1664-3224
ER -