Ginseng Compound Rg3 Rewires Tumor Macrophages and Boosts Immunotherapy in Mice

Ginsenoside Rg3, a triterpenoid glycoside derived from Panax ginseng, appears to fight colorectal cancer not by attacking tumor cells directly, but by reprogramming the immune cells that surround them. In a new study published in Cell Communication and Signaling, researchers report that Rg3 binds a glucose transporter on tumor-associated macrophages, shifts their metabolism, and thereby converts a notoriously immunosuppressive corner of the tumor microenvironment into one that recruits cancer-killing T cells. The work, released as an accepted manuscript shared early for faster access, remains preclinical, but its combination strategy produced striking results in mouse models, including enhanced responses to anti-PD-1 immunotherapy.

Tumor-associated macrophages, or TAMs, are the most abundant infiltrating immune cells in tumors, and in colorectal cancer they tend to adopt a polarization state that suppresses immune attack rather than mounting one. The authors set out to test whether the anti-tumor activity attributed to Rg3 depends on this macrophage-mediated immune suppression, a question they describe as previously largely unresolved.

To probe the mechanism, the team combined several models and technologies. They examined Rg3’s immunomodulatory effects in murine colorectal cancer models and in human three-dimensional organoid systems. To find the compound’s molecular target, they used MS-DARTS technology, then validated the candidate binding through CETSA thermal-shift assays, surface plasmon resonance, and molecular dynamics simulations. Metabolomic, proteomic, and transcriptomic profiling was used to map the metabolic and molecular consequences, and a macrophage-specific Glut1 knockout mouse model allowed the researchers to test whether the transporter was required for the observed effects.

The results converge on Glut1, the glucose transporter on macrophages. According to the study, Rg3 directly binds Glut1 on macrophages, which inhibits acetylation of the transporter mediated by the p300/CBP acetyltransferases and triggers metabolic reprogramming. This cascade reduces cellular itaconate levels and leads to enhanced phosphorylation of JAK1 and subsequent activation of the STAT1 signaling pathway.

Downstream of STAT1, the effects become visible to the immune system. The authors report that Rg3 promotes STAT1 nuclear translocation, increasing macrophage secretion of the chemokines CXCL10 and CXCL11. These chemokines facilitate the infiltration of CD8+ T cells into tumors. In this scheme, a ginseng-derived small molecule effectively flips macrophages from immunosuppressive gatekeepers into beacons that draw killer T cells into the tumor.

Functionally, the study reports that Rg3 inhibited colorectal cancer progression by modulating the immunosuppressive polarization of TAMs in a host immune-dependent manner, meaning the anti-tumor effect required an intact immune system rather than acting through direct tumor-cell toxicity alone. The macrophage-specific Glut1 knockout model was used to assess how Glut1 deficiency affects TAM polarization and the therapeutic efficacy of Rg3, tying the transporter to the compound’s mechanism.

Perhaps the most clinically suggestive finding concerns combination therapy. The researchers evaluated Rg3 together with anti-PD-1 antibody treatment and found that Rg3 enhanced the therapeutic effect of anti-PD-1 against colorectal cancer progression.

The authors conclude that Rg3 is a promising candidate for targeting TAM metabolism to reshape the immunosuppressive tumor microenvironment and combat colorectal cancer development. Important caveats remain. The evidence presented comes from mouse models and human organoid systems, not human patients, and the article was shared early as a peer-reviewed accepted version that is still subject to further editorial edits before the final version of record.

Subject of Research: Ginsenoside Rg3 targeting Glut1 acetylation on tumor-associated macrophages to reshape the colorectal cancer tumor microenvironment and enhance anti-PD-1 immunotherapy

Article Title: Ginsenoside Rg3 targets Glut1 acetylation to restrain immunosuppressive TAM polarization and potentiate anti-PD-1 therapy in colorectal cancer

Article References: Qian, C., Huang, Y., Zhi, Y., Luo, Y., Shao, L., Cheng, P., Zhong, C., Wan, L., Shen, Q., Lu, Y., & Zhao, Y. (2026). Ginsenoside Rg3 targets Glut1 acetylation to restrain immunosuppressive TAM polarization and potentiate anti-PD-1 therapy in colorectal cancer. Cell Communication and Signaling. https://doi.org/10.1186/s12964-026-03319-8

Image Credits: AI Generated

DOI: 10.1186/s12964-026-03319-8

Keywords: ginsenoside Rg3, tumor-associated macrophages, Glut1, colorectal cancer, anti-PD-1 immunotherapy, STAT1 signaling, CXCL10, CXCL11, CD8+ T cells, metabolic reprogramming, tumor microenvironment, microsatellite stable