Recurrence of tumors that are therapy-resistant is one of the major hurdles in cancer treatment, historically resistant clone were assumed to be either preexisting or emerge through mutation. Recently, it has become apparent that microenvironmental niches within a tumor may also play an important role in the acquisition of resistance. Blood vessel architecture within a tumor creates multiple regions of varying oxygen, nutrient, and proton concentration. These niches in turn select for different tumor cell phenotypes facilitating tumor heterogeneity and favoring more aggressive cells. Vascular density also affects immune cell extravasation and may drive selection for immune resistant tumor phenotypes. We constructed a multiscale model in order to examine the phenotypic adaptation of tumor cells to microenvironmental heterogeneity in untreated tumors as well as those undergoing various therapeutic regimes. Tumor cells, evolved along a continuum of proliferative, invasive, and immunosuppressive phenotypes, with selection pressures applied by pH, hypoxia, cytotoxic T lymphocytes, and therapeutic agents. The spatially explicit nature of the model reveals how spatial dynamics within the tumor, in addition to selection pressure from the microenvironment, is critical for the acquisition of resistance phenotypes. Furthermore, immune resistance can be acquired through several distinct routes. Finally, we show how understanding these evolutionary dynamics suggests novel treatment strategies that minimize the potential for rapid tumor recurrence.