Oral cancer pain is difficult to treat with limited efficacy or rapid development of tolerance and severe side effects of available medications. The immune system has been shown to play a critical role in controlling chronic pain, however, very few studies have explored its role in oral cancer pain. We have identified novel targets that have shown to play a significant role in mediating persistent inflammation in autoimmune and chronic inflammatory disease. The Lymphotoxin-beta receptor and its ligand LIGHT (TNFSF14), belong to the family of tumor-necrosis factor and have shown to be expressed in a variety of cells that make up the microenvironment. The current study explores the contribution of LIGHT and LTβR in mediating oral cancer pain. An orthotopic tongue cancer pain model using human oral squamous cell carcinoma (OSCC) cells were employed for all experiments. We determined effect of local injection of LIGHT and LTβR antagonistic antibody (LTβRIg) on tumor-induced pain behaviors including feeding behaviors and Von Frey thresholds in the face. Body weights and tumor volumes were also measured. Further, we determined expression of LTβR and LIGHT in several cell types within tumor-bearing tongues using immunohistochemistry. Our data showed that local injection of LIGHT reversed tongue-tumor induced reduction in feeding behavior and increased body weights compared to vehicle group. Conversely, injection of local LTβRIg worsened tumor-induced feeding behavior and decreased body weights compared to the control group. LIGHT and LTβRIg had no effect on tumor volumes. Anatomical analyses showed LTβR expression in cancer cells and stromal cells within the tumor and LIGHT expression in immune cells. Taken together, our data demonstrate that LIGHT/LTβR signaling may inhibit oral cancer-induced pain via modulating downstream signaling in OSCC cells and the associated stromal cells which in turn may control peripheral lingual sensory nerve activities. Title: LIGHT and Lymphotoxin targeting for the treatment of chronic orofacial pain conditions. R01 DE029187 from NIH/NIDCR.