Intimate communications within the tumor microenvironment: stromal factors function as an orchestra

Extensive studies of the tumor microenvironment (TME) in the last decade have reformed the view of cancer as a tumor cell-centric disease. The tumor microenvironment, especially termed the "seed and soil " theory, has emerged as the key determinant in cancer development and therapeutic resistance. The TME mainly consists of tumor cells, stromal cells such as fibroblasts, immune cells, and other noncellular components. Within the TME, intimate communications among these components largely determine the fate of the tumor. The pivotal roles of the stroma, especially cancer-associated fibroblasts (CAFs), the most common component within the TME, have been revealed in tumorigenesis, tumor progression, therapeutic response, and tumor immunity. A better understanding of the function of the TME sheds light on tumor therapy. In this review, we summarize the emerging understanding of stromal factors, especially CAFs, in cancer progression, drug resistance, and tumor immunity with an emphasis on their functions in epigenetic regulation. Moreover, the importance of epigenetic regulation in reshaping the TME and the basic biological principles underpinning the synergy between epigenetic therapy and immunotherapy will be further discussed.