 Lysophosphatidic acid, LPA, is a bioactive lipid which increases in concentration locally and systemically across different cancer types. This lipid can affect CD8-T cell immunosurveillance during tumor progression, but the precise mechanisms are still unknown. We have shown that LPA receptors, LPAR, signaling by CD8-T cells promotes tolerogenic states via metabolic reprogramming and potentiating exhaustive-like differentiation to modulate anti-tumor immunity. We also discovered that LPA levels predict response to immunotherapy and LPA-R5 signaling promote cellular states associated with exhausted phenotypes on CD8-T cells. Furthermore, we found that LPA-R5 regulates CD8-T cell respiration, proton leak, and reactive oxygen species. In conclusion, our study has revealed that LPA serves as a lipid-regulated immune checkpoint by modulating metabolic efficiency through LPA-R5 signaling on CD8-T cells. These findings offer important insights into the mechanisms governing adaptive anti-tumor immunity and demonstrate that LPA could be used as AT. This article was authored by Jekyllyn A. Turner, Malia A. Fredrickson, Mark D'Antonio, and others. We are article.tv, links in the description below.