〔Abstract〕 Objective To investigate the impact of tumor necrosis factor ligand superfamily member 13(TNFSF13) derived from M2 macrophages on temozolomide(TMZ) resistanceviaregulating interferon regulatory factor 8(IRF8) in glioblastoma(GBM) cells. Methods Immunohistochemistry(IHC) was used to detect the expression of TNFSF13 in normal brain tissues and GBM tissues. ELISA was used to measure the expression of TNFSF13 in the conditioned media(CM) of M0-type macrophages and M2-type macrophages. M0-CM and M2-CM were used to culture U251 sensitive(U251/S) and resistant(U251/R) cells. The TMZ treatment group was also treated with 800 μmol/L TMZ. The U251/R cells were divided into the following groups: con group, M2vector-CM group, M2vector-CM+TMZ group, M2TNFSF13-CM group, M2TNFSF13-CM+TMZ group, si-IRF8 group, and si-IRF8+M2TNFSF13-CM group. CCK-8 assay was used to detect cell viability and calculate the IC50value. Transwell assay was used to detect cell invasion. Flow cytometry was used to detect apoptosis. Western blot was used to detect the expression of IRF8. Nude mouse xenograft models were constructed and the nude mice were divided into the following groups: U251+M2si-NCgroup, U251+M2si-TNFSF13group, U251+M2si-NC+TMZ group, U251+M2si-TNFSF13+TMZ group. The tumor volume and mass of each group were measured, and IHC was used to detect the expression of TNFSF13 and CD206 in tumor tissues of each group. Results Compared with adjacent tissues and M0-CM, the expression of TNFSF13 was up-regulated in cancer tissues and M2-CM. Compared with the M0-CM group, the IC50value of TMZ and the number of cell invasions in U251/S and U251/R cells in the M2-CM group significantly increased(allP<0.05). Overexpression of TNFSF13 in M2 macrophages could promote the IC50value of TMZ in U251/R cells, promote cell invasion, and inhibit cell apoptosis(allP<0.05). Overexpression of TNFSF13 promoted the expression of IRF8, and knocking down IRF8 could attenuate the TMZ resistance of U251/R mediated by overexpression of TNFSF13.In vivostudies showed that knocking down TNFSF13 alone or combined with TMZ treatment significantly inhibited tumor growth and reduced the expression of TNFSF13 and CD206. Conclusion TNFSF13 derived from M2 macrophages promotes TMZ resistance in GBM cells by activating IRF8.