Radiotherapy is a widely employed technique for eradication of tumor using high-energy beams, and has been applied to approximately 50% of all solid tumor patients. However, its non-specific, cell-killing property leads to inevitable damage to surrounding normal tissues. Recent findings suggest that radiotherapy-induced tissue damage contributes to the formation of a pro-tumorigenic microenvironment. In the present study, we used two organ-targeted radiotherapy models to uncover the mechanisms underlying the development of the radiotherapy-induced microenvironment. Radiotherapy-induced tissue damage stimulates infiltration of monocyte-derived macrophages and their differentiation into M2 macrophages, ultimately leading to fibrosis and the formation of a pro-tumorigenic microenvironment. Notably, SRC family kinases (SFKs) emerged as crucial factors in the formation of the radiotherapy-induced pro-tumorigenic microenvironment. SFKs activation in epithelial cells and fibroblasts was triggered by direct exposure to irradiation or M2 macrophage cytokines. Remarkably, the administration of SFK-targeted inhibitors reversed myofibroblast activation, effectively ameliorating fibrosis and the pro-tumorigenic microenvironment in radiated tissues. Further, combined administration of radiotherapy and SFK-targeted inhibitors significantly enhanced the survival of tumor-bearing mice. Overall, reshaping the tissue microenvironment by targeting SFKs is a potential strategy for preventing metastasis and recurrence following radiotherapy. The finding that clinically imperceptible damage can trigger a pro-tumorigenic microenvironment suggests the need for combining SFK-targeted inhibitors with radiotherapy. This work was supported by the National Research Foundation of Korea (NRF) grant (RS-2024-00346965) funded by the Korea government.