Hirsutella sinensis Fungus Promotes CD8 + T Cell-Mediated Anti-Tumor Immunity by Affecting Tumor-Associated Macrophages-Derived CCRL2

Hirsutella sinensis fungus (HSF)is an artificial substitute for Cordyceps sinensis and has shown promising therapeutic effects in various diseases including cancer. Previous studies have demonstrated that HSF can affect macrophage polarization and activate systemic immune response. In our preliminary experiments, we validated that HSF inhibited the proliferation of lung cancer (LC) cells, but the underlying mechanism is elusive. We intended to explore the mechanism of HSF in promoting anti-tumor immunity. In vivo experiments were performed to confirm inhibitory effect of HSF on LC growth, and sequencing results revealed abnormal expression of CCRL2. Knockdown and overexpression of CCRL2 were conducted to investigate its effect on macrophage polarization, and co-culture with T cells was to assay the impact of HSF+CCRL2 on CD8+ T cell activation by flow cytometry. Overexpression of CCRL2 promoted macrophage polarization toward M1 and activated the proliferation and effector function of CD8+ T cells. HSF promoted CCRL2 expression and affected M1 polarization via CCRL2, which in turn affected CD8+ T cell-mediated anti-tumor immunity. Our study demonstrated that HSF promoted macrophage M1 polarization and activated CD8+ T cells via CCRL2, thereby inhibiting the progression of LC.