Abstract Purpose Macrophages involved in innate immunity and possess cytotoxicity via NO, ROS and pro-inflammatory cytokines, such as TNF-α and IFN-γ. But long-term effects of M1 macrophages on cancer cells, especially their tumoricidal activity, remain unclear. In our previous study, conditioned medium (CM) from M1 macrophages can induce A549 apoptosis and senescence, but detail mechanism is unexplored. Materials & Methods Lung cancer cell lines, A549 and H460, are cells with wild-type p53, but H1299 is p53-null. Cytokine and cDNA microarray were used to evaluate the content of M1 macrophages and their effects on A549 cell. Flow cytometry was assessed cell apoptosis; real-time PCR and Western blot were assessed the expression of identified genes and proteins. Clinical statistical analysis for predicting survival of lung cancer patients was applied by a published clinical microarray dataset. Results According to our previous results of cDNA microarray, several significantly differential genes were the down-stream of p53, the important initiator for apoptosis. After M1 CM treatment, A549 and H460 cells went apoptosis and p53 was abundantly accumulated. But cell death was not observed in H1299 cells, unless exogenous wt-p53 was expressed and M1 CM treated. Another transcription factor STAT1 was also up-expressed at translational and transcriptional levels after M1 CM stimulation. STAT1 may interact and assist with p53 to cause cell death. IFN-γ which is a well known cytokine for STAT1 activation highly expresses in M1 macrophages, but antibody neutralization can not reverse cell apoptosis. M1 macrophages from human PBMCs also had tumoricidal activity for A549. Moreover, the M1/M2 gene signature from A549 cDNA microarray can predict the patients' survival. Conclusion Accumulated data show that p53 and STAT1 are the main tumoricidal regulators induced by M1 macrophages in long-term culture and that is IFNs independent signaling pathway. Those data imply that M1 macrophage plays an important role in the immune surveillance for cancer progression. That may be a potential immunol target therapy. Citation Format: Yi-Jing Hsiao, Kang-Yi Su, Jian-Wei Chen, Sung-Liang Yu. M1 macrophages suppress tumorigenesis via accumulated p53 and upregulated STAT1 in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1069. doi:10.1158/1538-7445.AM2014-1069