Targeting Tumor Microenvironment and Metabolism to Overcome Radiation Resistance.

The tumor microenvironment comprises multiple different cell types and structural and functional components, and defines a unique tumor milieu on the individual tumor level. Several biological processes in the microenvironment are pivotal for tumor growth, like the formation of an intact tumor vasculature and the composition of the extracellular matrix. Furthermore, tumor heterogeneity also derives from the complex and dynamic interactions of the tumor cells with the stromal compartment during tumor growth and in response to treatment, and thereby represents a major treatment hurdle. Here we give an overview of the different entities of the tumor microenvironment and present their role in radiation resistance. Dynamic changes in response to irradiation will be outlined, and relevant approaches to target critical elements of the tumor microenvironment will be discussed. We are only now starting to understand how these different entities cooperate biologically, and thereby determine tumor aggressiveness and treatment resistance on the individual level. At the same time, these dynamic and even treatment-induced interactions within the tumor represent promising targets for novel combined treatment modalities with radiotherapy.