In the past decade, immunotherapy has been the most promising treatment for gastrointestinal tumors. But the low response rate and drug resistance remain major concerns. It is therefore imperative to develop adjuvant therapies to increase the effectiveness of immunotherapy and prevent drug resistance. Ginseng has been used in Traditional Chinese medicine as a natural immune booster for thousands of years. The active components of ginseng, ginsenosides, have played an essential role in tumor treatment for decades and are candidates for anti-tumor adjuvant therapy. They are hypothesized to cooperate with immunotherapy drugs to improve the curative effect and reduce tumor resistance and adverse reactions. This review summarizes the research into the use of ginsenosides in immunotherapy of gastrointestinal tumors and discusses potential future applications.
Background Approximately 1.8 million new cases colorectal cancer (CRC) are diagnosed each year, and despite recent advances in treatment approaches, mortality from CRC remains high. The objective of this study was to investigate the therapeutic effects and mechanism of the ginsenoside Rg5 against CRC tumors.Methods Different animal models of colorectal cancer (xenograft, syngeneic, humanized patient-derived xenograft) were used to determine the pharmacological effects of Rg5 on CRC. We performed Human Proteome chip, Pulldown assays, RNA-sequencing (RNA-seq), Single cell RNA-sequencing (scRNA-seq) and Microscale thermophoresis (MST) analysis to identify the against CRC molecular mechanism of Rg5.Results We found that Rg5 can inhibit tumor progression in both syngeneic and patient-derived xenograft subcutaneous CRC tumor-bearing immunocompetent mice. RNA-sequencing analysis indicated that NF-κB signaling decreases while the proportion of tumor-resident Cd8+ T cells increases under Rg5 treatment in CRC cells from tumor-bearing mice. Microscale thermophoresis binding assays identified mannose-6-phosphate receptor (M6PR) and nuclear factor kappa B subunit 2 (NFKB2) as primary targets of Rg5. Rg5 increases M6PR protein levels in CRC cells and binds to NFKB2, reducing its transcriptional activation of PD-L1, which in turn downregulates NFKB2 levels. The resulting increase in CD8+T cells in CRC tumors profoundly enhances the efficacy of immune checkpoint PD-1 antibody blockade therapy. Conclusion Our findings indicate strong clinical potential for Rg5 in combination with Programmed cell death protein 1(PD-1) blockade for treating CRC. By reducing Programmed cell death 1 ligand 1 (PD-L1) transcription via interaction with NFKB2, Rg5 increases tumor-resident CD8+T cell populations, resulting in boost enhanced tumor response to PD-1 blockade immunotherapy.
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