Tumor-associated macrophages (TAM) constitute up to 50–80% of stromal cells in breast cancer (BC), and are correlated with poor prognosis. As epidermal growth factor receptor (EGFR) is overexpressed in 60–80% of patients with triple negative breast cancer (TNBC), photoimmunotherapy (PIT) with cetuximab-targeted gold nanorods (CTX-AuNR) is an attractive therapeutic strategy for TNBC. The 3D cell culture model can mimic drug resistance conferred by the tumor microenvironment and its 3D organization; therefore, TAM and non-TAM embedded TNBC spheroids were constructed to evaluate the therapeutic efficacy of CTX-AuNR plus near infrared (NIR) irradiation. Cytotoxicity, reactive oxygen species (ROS) generation, and protein expression were compared in TNBC (± TAM) spheroids. The IC₅₀ values of doxorubicin (DOX) in TAM-embedded TNBC spheroids were significantly higher than those in TNBC spheroids, demonstrating drug resistance, which could be explained by activation of IL-10/IL-10 receptor/STAT3/Bcl-2 signaling. However, 3D in vitro and in vivo results demonstrated that the efficacy of CTX-AuNR plus NIR irradiation was not significantly different in (± TAM) embedded TNBC cells. By enhancing ROS generation, CTX-AuNR plus NIR irradiation reprogrammed TAM polarization to the M1 anti-tumor phenotype, as indicated by macrophage mannose receptor (MMR) downregulation. Thus, CTX-AuNR plus NIR can serve as a potent PIT strategy for treating EGFR-overexpressing TNBC cells.