Age plays a crucial role in the interplay between tumor and host; with further perturbations induced by irradiation. Proton irradiation on tumors induces biological modulations including inhibition of angiogenic and immune factors critical to hallmark processes impacting tumor development in addition to physical targeting advantages. These advantages have provided promising results for proton therapy in cancer. Additionally protons have implications for carcinogenesis risk of space travel (due to the high proportion of high energy protons in space radiation). Through a systems biology approach we investigated how host tissue (i.e. splenic tissue) of tumor-bearing mice is altered with age with or without whole-body proton exposure. Transcriptome analysis was performed on splenic tissue from adolescent (68 day) versus old (736 day) C57BL/6 male mice injected with Lewis lung carcinoma cells with or without three fractionations of 0.5Gy (1GeV) proton irradiation. Global transcriptome analysis indicated that proton irradiation of adolescent hosts caused significant signaling changes within splenic tissues that support carcinogenesis within the mice as compared to old subjects. Increases in cell cycling and immunosuppression in irradiated adolescent hosts with CDK2 MCM7 CD74 and RUVBL2 as the key players were involved in the regulatory changes in host environment response (i.e. spleen). These results suggest a significant biological component to proton irradiation operative through host age that would indicate a modulation of host s ability to support carcinogenesis in adolescence and the bestowal of resistance to immunosuppression carcinogenesis and genetic perturbation by old age.