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Huaier enhances the antitumor effects of CDK 4/6 inhibitor by remodeling the immune microenvironment and gut microbiota in breast cancer

Yifei Wang,Xiaolong Wang,Wenhao Li,Hanwen Huang,Chenyu Di,Qifeng Yang

Ethnopharmacological relevance Trametes robiniophila Murr (Huaier), a traditional Chinese medicine (TCM), has shown promising effects as a complementary therapy in the treatment of multiple kinds of cancers. Aim of the study This study aimed to systematically evaluate whether Huaier could enhance the antitumor effects of palbociclib, a highly selective CDK4/6 inhibitor. Materials and methods A breast cancer xenograft mouse model was constructed to assess the anticancer effects of Huaier and palbociclib. Transcriptomic analysis was performed to identify the differentially expressed genes and associated pathways. Flow cytometry, immunofluorescence and immunohistochemical staining were then conducted to observe the infiltration of immune cells in the tumor microenvironment (TME). The composition of the gut microbiota was explored through 16S rDNA sequencing, and a pseudosterile mouse model was established to verify the contribution of the gut microbiota to the antitumor effects of Huaier and palbociclib. Results Oral administration of Huaier enhanced the antitumor effects of palbociclib in breast cancer. Transcriptomic analysis of tumor tissues revealed that the differentially expressed genes were related to immune functions. Indeed, the addition of Huaier to palbociclib therapy further increased the ratio of CD8 + /CD3 + T cells and the abundance of GzmB + CD8 + T cells in the TME. Mechanistically, sequencing of 16S rDNA revealed that Huaier reshaped the gut microbiota composition in favor of Akkermansia , which positively modulated antitumor immune responses. The pseudosterile mouse model verified the necessity of the gut microbiota for the synergistic effect of Huaier on palbociclib. Furthermore, butyrate, a metabolite of Akkermansia , synergized with palbociclib to suppress tumor progression and promote the infiltration of CD8 + T cells in the TME. Conclusions Our data suggested that Huaier augmented the antitumor effects of palbociclib by increasing the abundance of Akkermansia in gut microbiota, which contributed to the enhancement of anti-tumor immunity. Consequently, combining palbociclib with Huaier may serve as a promising strategy for the treatment of breast cancer.