The mechanism by which tumor microenvironment derived cytokine network modulates therapy response is of great concern in lung cancer but is not completely understood. In this study, we evaluated the effects of tumor necrosis factor α (TNF-α) and insulin-like growth factor 1 (IGF-1) on response of lung cancer cell lines to ionizing radiation (IR). While TNF-α increased radio sensitivity and inhibited cell migration, treatment with IGF-1 promoted cell growth and increased migration. These effects of TNF- α were mediated by increased immediate activation of stress-activated protein kinases (SAPK)/jun amino-terminal kinases (JNK) and p38. IR induced DNA damage was increased by TNF- α and not altered by IGF-1. However, in IGF-1 treated cells, there was decreased γ- H2AX along with an increase in mitotic index, resulting in abnormal chromosomal segregation in the cells. Bio informatics analysis of 982 lung cancer patients revealed that higher expression of TNF- α was associated with low risk of cancer progression while overexpression of IGF-1 was correlated with high risk. Collectively, these results reveal that the cytokines in the tumor microenvironment differentially modulate radiation therapy through a variety of signaling mechanisms.