SPP1 and breast cancer: Taken together, we propose the following mechanisms of TAM-related protumor signaling: (1) Cytotoxic signals from TILs induce chemokine production, such as CCL5, in breast cancer cells; (2) Infiltrated TAMs secret protumor soluble factors, including osteopontin, heparin-binding epidermal growth factor-like growth factor, and IL-6; and (3) TIL-derived factors, including IFN-γ and GM-CSF, induce PD-1 ligands, which in turn suppress the anti-cancer effects of TILs (Supplemental Fig. 5).