Significance While there is a clear understanding of how invariant NKT (iNKT) cells are activated in foreign infection, it remains unclear how they are activated during sterile inflammation, including cancer, where they have a well-defined role in tumor immunosurveillance. Here we elucidate a mechanism by which iNKT cells are activated through 1) the presentation of self-lipid antigens by endoplasmic reticulum-stressed antigen-presenting cells and 2) enhanced functional avidity driven by actin cytoskeletal remodeling. We further provide evidence that this mechanism of activation is at play in tumor settings. Here we describe a physiological context, relevant to human health and disease, that drives the presentation of immunogenic self-lipids to activate iNKT cells during sterile inflammation.