Summary Unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress in response to protein misfolding. Three master regulators control the UPR: IRE1α, PERK, and ATF6. The primary goal of UPR is to induce transcriptional and translational programs to maintain ER homeostasis for cell survival. Thus, dysfunctional UPR signaling has been shown to contribute to various health conditions including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. The ER stress pathways have been studied in cancer cells extensively, but have been overall understudied in T-cell immunity and tolerance. There are several knowledge gaps in understanding the impacts of the ER stress pathways in T-cell immunity against cancer. Our long-term goal is to develop novel strategies through targeting the ER stress pathways for improving cancer immunotherapy of human malignancies. the overall objectives of this application are to provide critical information towards more understanding the impacts of ER stress pathways on immune responses against cancer, which will eventually help to fulfill our long-term goal. Our central hypothesis is that the IRE-1α/XBP-1 and PERK/CHOP pathways differentially regulate CD4 and CD8 anti-tumor responses in microenvironment dependent manner. The hypothesis has been formulated based on preliminary data generated from in vitro and in vivo experiments using genetically modified mice with T-cell conditional knock-out (KO) for XBP-1, PERK or both. This hypothesis will be tested in the following two Specific Aims: 1) To define the role of XBP-1 and PERK in T-cell mediated graft-versus-host (GVH) and graft- versus-leukemia (GVL) responses; 2) To define the impact of XBP-1 and PERK in T-cell immunity against tumor. The proposed study is expected to provide a strong guidance for improving T-cell based cancer immunotherapy by targeting the ER stress pathways and to provide a solid foundation for further studying underlying mechanisms of ER stress pathways in regulating T-cell immunity.