This study demonstrates for the first time that targeting CD115 on cancer host cells using a blocking mAb (i) depletes CD163+ M2-type TAMs and inhibits tumor growth in either ectopic or spontaneous cancer models; (ii) has therapeutic activity at early or late cancer stages in a model recapitulating the progression of human breast cancer, where it potentiates the effect of chemotherapy; and (iii) inhibits metastasis-induced bone degradation by decreasing osteoclast numbers. The gene discussed is CD163; the disease is cancer.