Cancer therapy has developed around the concept of killing, or stopping the 
growth of, the cancer cells. Molecularly targeted therapy is the modern 
expression of this paradigm. Increasingly, however, the realization that the 
cancer has co-opted the normal cells of the stroma for its own survival has led 
to the concept that the tumor microenvironment (TME) could be targeted for 
effective therapy. In this review, we outline the importance of tumor-associated 
macrophages (TAM), a major component of the TME, in the response of tumors to 
cancer therapy. We discuss the normal role of macrophages in wound healing, the 
major phenotypes of TAMs, and their role in blunting the efficacy of cancer 
treatment by radiation and anticancer drugs, both by promoting tumor 
angiogenesis and by suppressing antitumor immunity. Finally, we review the many 
preclinical studies that have shown that the response of tumors to irradiation 
and anticancer drugs can be improved, sometimes markedly so, by depleting TAMs 
from tumors or by suppressing their polarization from an M1 to an M2 phenotype. 
The data clearly support the validity of clinical testing of combining targeting 
TAMs with conventional therapy. Clin Cancer Res; 23(13); 3241-50. ©2017 AACR.