Nuclear receptors as modulators of the tumor microenvironment

Over the past several decades of cancer research, the inherent complexity of tumors has become increasingly appreciated. In addition to acquired cell-intrinsic properties, tumor initiation and growth is supported by an abundance of parenchymal, inflammatory, and stromal cell types, which infiltrate and surround the tumor. Accumulating evidence shows that numerous components of this supportive milieu, referred to collectively as the tumor microenvironment, are indeed critical during the process of multistep tumorigenesis. These findings highlight the important interplay between neoplastic cells and tumor-associated cell types, and suggest that therapy should target both neoplastic cells and supportive stromal cells to effectively attenuate tumor growth. The nuclear receptor superfamily encompasses a druggable class of molecules expressed in numerous stromal and parenchymal cell types, whose established physiologic roles suggest their potential as therapeutic and preventive targets in the context of the reactive tumor microenvironment. In this minireview, we discuss recent evidence that tumor-associated inflammation, angiogenesis, and fibrosis can be modulated at the transcriptional level by nuclear receptors and their ligands. As these processes have been widely implicated in cancer initiation, progression, and resistance to current therapy, nuclear receptor ligands targeting the tumor microenvironment may be potent antitumor agents in combination therapies, including for preventing cancer development within high-risk populations.