iNKT cells have a prominent role in anti-tumor immune responses. Indeed, iNKT cell deficient mice have a higher incidence of methylcholanthrene-induced sarcoma, indicative of defective immune-surveillance.1 However, it is unclear how iNKT cells become activated in the context of cancer. Accumulating evidence implicates endoplasmic reticulum (ER) stress in the development and progression of many diseases, including cancer. ER-stress triggers the unfolded protein response (UPR). In turn, the UPR activates numerous signaling pathways, many of which overlap with lipid biosynthetic and immune response pathways. This intersection raises the possibility that the UPR modulates endogenous lipid antigen presentation on CD1d⁺ myeloid populations and CD1d⁺ tumor cells, resulting in enhanced iNKT cell activation in cancer. To investigate this hypothesis, iNKT cells were co-cultured with monocyte-derived dendritic cells or THP1 cells pre-treated with thapsigargin. Thapsigargin-treated cells activated iNKT cells in a CD1d-dependent manner. Given that CD1d expression levels do not change between untreated and thapsigargin-treated antigen presenting cells, we are identifying the activating self-lipid antigen(s) preferentially loaded onto CD1d molecules in ER-stressed antigen presenting cells and through molecular techniques are investigating which branch of the UPR is responsible for changes in the lipid antigen profile of ER-stressed cells.