miR-let-7a suppresses gastric cancer peritoneal metastasis through IRS2-mediated M1 macrophage polarization and direct inhibition of gastric cancer cells.

Gastric cancer, the fifth most prevalent and lethal malignancy worldwide, represents a significant public health challenge that necessitates urgent intervention. Peritoneal metastasis accounts for the majority of recurrences and fatalities following curative surgery for advanced gastric cancer. This study demonstrated that miR-let-7a inhibits gastric cancer peritoneal metastasis through dual mechanisms. Firstly, it promotes the polarization of macrophages to the M1 phenotype by targeting the 3'UTR of IRS2 mRNA, resulting in reduced IRS2 expression and phosphorylation and consequent suppression of the PI3K/AKT signaling pathway. Secondly, macrophages can release miR-let-7a to gastric cancer cells, directly inhibiting their malignant metastatic potential. Our findings suggest that miR-let-7a and IRS2 are promising targets for the development of immunotherapy for gastric cancer. Moreover, establishing systems for the endogenous delivery of miR-let-7a may provide innovative strategies to impede gastric cancer progression.