Our study indicated that PIK3CAmut can induce immune evasion of LBC by recruiting MDSCs through the 5‐LOX‐dependent AA pathway, and a PI3K inhibitor could synergize with ICB therapy by systematically recovering the immune competent TIME by excluding MDSCs and recruiting cytotoxic T cells. This evidence concerns the gene PIK3CA and CDH1-related diffuse gastric and lobular breast cancer syndrome.