Abstract
Background: Chemotherapy has a broad-spectrum anti-tumor effect and is still the core strategy for cancer treatment. However, the side effects caused by its cytotoxicity, the chemoresistance caused by tumor heterogeneity and abnormal microenvironment seriously restrict the efficacy of chemotherapy. Metformin presents the ability to sensitize chemotherapy by interfering with metabolic processes of tumor cells. However, as a dynamic process, metabolic intervention requires a specific time sequence law to optimize its role. Methods: Different administration sequences were screened by in vitro experiments to determine the optimal sequence of metformin and docetaxel. The anti-tumor effect of administration sequence in vivo was investigated in mouse models. The therapeutic advantages were comprehensively evaluated by tumor size, weight change, and survival rate. The immunofluorescent staining and transcriptome analysis were performed to study the mechanisms of the sequential administration strategy. Results: Compared with the subsequent administration and concurrent administration, pretreatment with metformin exhibited a stronger ability toward cell cycle arrest and tumor inhibition with low-dose docetaxel. Moreover, this pre-administration sequence could enhance the anti-tumor immune responses and prevent postoperative recurrence. Conclusions: The optimized chemotherapy sensitization mediated by metabolic intervention required an appropriate administration sequence, which also strengthened the anti-tumor immune responses.