Feiwei Mixture Exerts Antitumor Activity Against Non‐Small Cell Lung Cancer via Regulating NR1D1‐Mediated Immune Cell Infiltration

ABSTRACT Feiwei Mixture (FWHJ), a hospital preparation for lung cancer, lacks a defined mechanism of action. Using Lewis lung carcinoma (LLC) tumor‐bearing mice and an LLC‐CD8 ⁺ T cell co‐culture model, we evaluated the effects of FWHJ on tumor growth, T cell infiltration, and apoptosis. Key signaling molecules (NR1D1, cGAS‐STING, SOCS3‐JAK‐STAT3) and chemokines were analyzed using Western blot, flow cytometry, and immunoassays. Further knockout of NR1D1 confirmed its critical role in mediating the anti‐tumor effects of FWHJ. FWHJ dose‐dependently inhibited tumor growth in mice and enhanced CD4 ⁺ /CD8 ⁺ T cell infiltration. It upregulated NR1D1, SOCS3, and the cGAS‐STING pathway, while suppressing JAK‐STAT3 signaling, leading to increased CCL5, CXCL10, and IFN‐α. In co‐culture model, FWHJ‐containing serum promoted LLC cell apoptosis and suppressed malignant progression, recapitulating the signaling alterations observed in vivo. Crucially, NR1D1 knockout abolished the therapeutic effects of FWHJ. FWHJ inhibits non‐small cell lung cancer (NSCLC) by activating NR1D1 to stimulate the cGAS‐STING pathway and suppress the JAK‐STAT3 signaling axis, thereby enhancing anti‐tumor immunity. This study provides a foundation for further investigation into the anti‐tumor mechanisms of FWHJ and establishes a scientific basis for its potential application in lung cancer therapy.