In conclusion, our findings demonstrate how: (i) the Ob/ObR signaling impacts the biology of breast cancer since its drastic downregulation induces a less aggressive tumor phenotype; (ii) Ob/ObR signaling knockdown contributes to reprograming the recruited macrophages by breast cancer cells by inducing a lower expression of cytokines and immunosuppressive markers concomitantly with their restored capability to engulf tumor cells. The gene discussed is LEP; the disease is breast cancer.