Our ability to control and eradicate cancer has advanced with new combinations of surgery, chemotherapy, irradiation therapy and recently, immunotherapy. The concept of a single cancer therapy has passed with each new discovery revealing the complexity of the genetics and immunology of the tumor microenvironment. Understanding which combination of standard and emerging therapies that can provide long lasting remission of each particular cancer is paramount. Here we review the capacity of radiation therapy (RT) combined with immune checkpoint inhibitors to induce a complete response in mammary carcinoma and melanoma (1,2) and the evaluation of therapy mechanism of action using intravital microscopy. Current tools and approaches to evaluate mechanism of action of therapies have been limited, but real time intravital imaging offers prospects of enhancing our knowledge.