Complexed siRNA stable up to 24 h in 50% serum. M2pep significantly increased M2 uptake, reduction of CSF-1R mRNA (~50%), and reprogramming to M1 (~50%). Production of M1 factors was accompanied by cancer cell apoptosis. Increased tumor accumulation was observed 12 h after administration (3.5-fold) when compared with non-targeted formulation. Reduction of tumor was accompanied by immune remodeling of TME, and redistribution of immune cells and factors was observed. Here, CSF1R is linked to cancer.