Abstract Lymphotoxin beta Receptor (LTβR) belongs to the Tumor Necrosis factor (TNF) receptor superfamily and was originally identified to be critical for the development and maintenance of secondary lymphoid architectures. However, it is increasingly appreciated that the LTβR signaling pathway is involved in induction of extrinsic apoptotic cell death in tumor cells. Strikingly, it was recently observed that sustained expression of LTβR ligands also promote tumor development via a NF-κB-dependent mechanism. Thus, LTβR could function as two-edged sword. There are two physiological ligands, LTα1LTβ2 and LIGHT, that engage the LTβR to initiate signaling transduction. These two ligands are known to be expressed in immune cells. However, whether immune cells use these two ligands to suppress tumor development is unknown. In this study, we observed that LTβR protein in expressed in all tumor cell lines examined and in human colon carcinoma and sarcoma specimens. Engagement of the LTβR with LTβR-specific agonist mAbs activated both the canonical and alternative NF-κB signaling pathways in tumor cells. However, these agonist mAbs at the same time also effectively suppressed the growth of colon carcinoma, melanoma, mammary carcinoma and sarcoma cells in vitro, suggesting that the LTβR-mediated apoptosis signaling pathway overpowers the LTβR-initiated NF-κB signaling pathways to yield an overall tumor suppressive effect. Furthermore, both LTα1LTβ2 and LIGHT were activated in tumor-infiltrating macrophage, NK and T cells. Chimera mice with LTα-, LIGHT- or both LTβ and LIGHT-deficient immune cells exhibited significantly high incidence of MCA-induced tumor and greater tumor growth than chimera mice with wt immune cells. Furthermore, double-deficiency of LTβ and LIGHT in the immune cells resulted in significantly higher tumor incidence and greater tumor growth than LTα-deficiency alone. Taken together, our data suggest that LTβR mediates an immune cell-exerted anti-tumor effector mechanism in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4764. doi:10.1158/1538-7445.AM2011-4764