Current paradigms of cancer-centric therapeutics are usually not sufficient to eradicate the malignancy, while cancer stroma may prompt tumor relapse and therapeutic resistance. Among all the stromal cells that populate the tumor microenvironment, tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs) and tumor-infiltrated lymphocytes (TILs) are the most abundant and are critically involved in cancer progression. Tumor stromal cells regulate the biology of tumor cells via cell-cell contact, numerous regulatory factors and synthesizing or remodeling the extracellular matrix, and thus affect cancer initiation and development. Therefore, recent characterization of tumor microenvironment brings stroma-targeting therapies for cancer treatment onto the agenda. In our studies, we not only underscore the contribution of tumor stroma components to cancer progression, but also highlight the relevant translational advances and potential therapeutic strategies that target tumor soil for cancer treatment.