Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance

The tumor microenvironment (TME) is a complex and ever-changing "rogue organ" composed of its own blood supply, lymphatic and nervous systems, stroma, immune cells and extracellular matrix (ECM). These complex components, utilizing both benign and malignant cells, nurture the harsh, immunosuppressive and nutrient-deficient environment necessary for tumor cell growth, proliferation and phenotypic flexibility and variation. An important aspect of the TME is cellular crosstalk and cell-to-ECM communication. This interaction induces the release of soluble factors responsible for immune evasion and ECM remodeling, which further contribute to therapy resistance. Other aspects are the presence of exosomes contributed by both malignant and benign cells, circulating deregulated microRNAs and TME-specific metabolic patterns which further potentiate the progression and/or resistance to therapy. In addition to biochemical signaling, specific TME characteristics such as the hypoxic environment, metabolic derangements, and abnormal mechanical forces have been implicated in the development of treatment resistance. In this review, we will provide an overview of tumor microenvironmental composition, structure, and features that influence immune suppression and contribute to treatment resistance.