Shengxian decoction suppresses malignant progression of lung adenocarcinoma by enhancing CD8⁺ T cell function via the...

Shengxian Decoction (SXD), a traditional Chinese herbal formula, has demonstrated significant clinical efficacy against lung adenocarcinoma (LUAD). However, its exact mechanisms of action remain to be elucidated. This study aimed to establish an animal model capable of simulating the dynamic progression of LUAD to investigate the anti-tumor effects and immunomodulatory mechanisms of SXD.

A TK (Trp53^-/-; Kras^G12D) LUAD mouse model was established by subcutaneously transplanting CRISPR/Cas9-edited mouse lung organoids into immunocompetent C57BL/6 mice. The model was characterized by histopathology, RT-qPCR, T7E1 assay, and transcriptomic analysis. Potential mechanisms of SXD were investigated through an integrated approach combining UHPLC-MS/MS, network pharmacology, molecular docking, and eQTL-based Mendelian randomization. Core targets and key signaling pathways were further evaluated by in vivo transcriptomic analysis, multiplex immunofluorescence, flow cytometry, an in vitro CD8⁺ T-cell coculture model, and surface plasmon resonance (SPR) analysis.

An immunocompetent TK-LUAD mouse model was successfully established, showing the dynamic pathological progression of LUAD and accompanying changes in immune infiltration. SXD treatment significantly delayed malignant progression in this model and was associated with modulation of the tumor immune microenvironment, as reflected by increased CD8⁺ T-cell infiltration and elevated levels of the cytotoxic effector molecules TNF-α, IFN-γ, and GZMB. Integrative analyses prioritized FYN as a candidate target potentially involved in SXD-mediated immunomodulation. SPR analysis showed concentration-dependent binding of representative SXD-derived compounds, including secoisolariciresinol, berberine, and acacetin, to FYN, providing additional support for direct target engagement. Further in vivo and in vitro experiments indicated that SXD enhanced the cytotoxic function of CD8⁺ T cells by activating the FYN-PI3K/AKT signaling pathway.

This study establishes an immunocompetent animal model for investigating LUAD progression and associated changes in the tumor immune microenvironment. In addition, this study provides evidence suggesting that the antitumor activity of SXD may be associated with FYN-related activation of the PI3K/AKT signaling pathway and subsequent enhancement of CD8⁺ T cell function. These findings provide a theoretical and experimental basis for further investigation of SXD as a potential therapeutic strategy for LUAD.