Abstract
The tumor microenvironment (TME) has now become a fundamental concept in oncology research, as it changes the traditional viewpoint of tumors as an autonomously functioning assembly of cancer cells. In this review, we evaluate recent advances in the understanding of the bidirectional crosstalk between the malignant cells and the neighboring, but non-malignant, stromal/immune cells. The roles of stromal cell subsets – mesenchymal stem cells, endothelial cells, and cancer-associated fibroblasts – as well as immunosuppressive immune cell populations, such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells, are considered. Furthermore, the mechanisms underlying the interactions of tumor-derived molecules, metabolic modifications, and exosome signaling with extracellular matrix (ECM) and tumor immune modulation that enable tumor evasion, angiogenesis, and pre-metastasis niche formation are discussed. As a result, we discuss the current state of several therapeutic possibilities, including vascular normalization, ECM disruption, metabolic targeting, and sophisticated nanotechnology-based drug delivery platforms. This review provides evidence that, in order to counteract TME-driven tumor progression, it is vital to develop combinatorial treatments targeting multiple aspects of microenvironmental networks, which form a necessary basis.