Tumor-associated macrophages (TAMs) are the essential components of the tumor microenvironment. TAMs originate from blood monocytes and undergo pro- or anti-inflammatory polarization during their life span within the tumor. The balance between macrophage functional populations and the efficacy of their antitumor activities rely on the transcription factors such as STAT1, NF-κB, IRF, and others. These molecular tools are of primary importance, as they contribute to the tumor adaptations and resistance to radio- and chemotherapy and can become important biomarkers for theranostics. Herein, we describe the major transcriptional mechanisms specific for TAM, as well as how radio- and chemotherapy can impact gene transcription and functionality of macrophages, and what are the consequences of the TAM-tumor cooperation.