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To evaluate the antitumor role of genes B7.2 and IL18, the radiation-inducible dual-gene coexpression plasmid pEgr-IL18-B7.2 was constructed and its effects on tumor were detected both in vitro and in vivo. After the introduction of pEgr-IL18-B7.2 into B16 melanoma cells, followed by X-ray irradiation, higher expression levels of B7.2 and IL18 compared with control were found both by flow cytometry and enzyme-linked immunosorbent assay. It was shown that even low-dose irradiation was able to induce their expression, which could be tightly regulated either by giving cells different doses of radiation or the same dose at different time points. pEgr-IL18-B7.2 was then packaged with liposome and injected into melanoma tumor-bearing mice. The tumors received 5 Gy of local X-ray irradiation every other day for a total of five treatments. B16 tumor growth slowed significantly when treated with pEgr-IL18-B7.2 plus X-radiation versus either treatment separately. Both 1 and 3 days after the last irradiation the group of mice with combined gene and radiation therapy showed significantly higher tumor necrosis factor (TNF)-α secretion in peritoneal macrophages, upregulated splenic cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, and higher interferon (IFN)-γ secretion than those in either individual treatment group or the control group. The stimulation of host anticancer immunity by increased secretion of IL-18 and upregulated immunogenicity of the tumor cells by increased expression of B7.2 on their surface, in addition to the direct effect of local X-irradiation on the tumor cells, may contribute to the novel effect of the combined therapy.