In patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy. Display omitted •IL-6 suppresses hepatic ketogenesis in pre-cachectic, tumor-bearing mice•During caloric deficiency, hypoketonemia triggers marked glucocorticoid secretion•Glucocorticoids, induced by metabolic stress, suppress intratumoral immunity•Stress-induced glucocorticoids cause failure of cancer immunotherapy Flint and Janowitz et al. reveal the intricate links between cancer cachexia, hepatic metabolism, and tumor immunology. They find that tumor-induced IL-6 suppresses hepatic ketogenesis, and during caloric deficiency, this triggers marked glucocorticoid secretion. This hormonal stress response suppresses intratumoral immunity and causes failure of anti-cancer immunotherapy.