Ovarian carcinoma is an aggressive cancer that is refractory to standard treatments and all current forms of immunotherapy. Like other aggressive tumors, ovarian tumors have evolved strategies to suppress recognition by the immune system. Dr. Juan Cubillos-Ruiz and his team at Cornell University have shown that the ovarian cancer tumor microenvironment (TME) can inhibit adaptive immunity by provoking an endoplasmic reticulum (ER) stress response in tumor infiltrating T cells through activation of the IRE1α-XBP1 pathway. TME-modulated nutrient restriction of T cells causes an accumulation of misfolded proteins, inducing ER stress that triggers metabolic alterations, changes in chromatin structure, and reduced tumor cell killing. In a first phase ASPIRE project, scientists in the Cubillos-Ruiz lab demonstrated that inhibition of the IRE1α-XBP1 pathway in T cells causes a delay in tumor progression in pre-clinical animal models. Building upon these observations in a second phase ASPIRE project, Cubillos-Ruiz and team will assess the impact of ER stress-induced metabolic changes on T-cell chromatin architecture to determine whether epigenetic reprogramming alters T-cell function. They will complement these analyses by assessing the impact of IRE1α-XBP1 disruption on the efficacy of immune checkpoint inhibitors as well as on the function of ovarian cancer-reactive T-cell therapies introduced into cancer models. The results of these efforts will lay the foundation for development of ER stress response-targeting drugs that could be combined with immunotherapies to improve outcomes in patients with immune-evasive cancers such as ovarian cancer.