Abstract Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and enable survival in starvation. Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect manifested by starvation intolerance and gradual loss of white adipose tissue, liver glycogen, and muscle mass. Cancer cells benefit from autophagy as deletion of essential autophagy genes impairs spontaneous tumor growth in autochthonous cancer models. Tumor cell autonomous autophagy is required to recycle macromolecules to sustain mitochondrial substrate supply and thereby energy and nucleotide pools essential for survival during nutrient limitation. In addition to promoting tumor cell survival, autophagy in the host also promotes tumorigenesis. Host-specific Atg7 or Atg5 deletion impairs growth of multiple different allografted tumors, by preventing the release of Arginase 1 from hepatocytes. Arginase 1 degrades circulating arginine that is essential for the growth of tumors, most of which are auxotrophic for arginine. Thus, autophagy sustains both tumor cell and host metabolism to enable tumor growth. In tumors with a high neoantigen load that can be recognized and killed by T cells, autophagy suppresses an antitumor T-cell response. Autophagy prevents tumor killing by T cells by suppressing production of interferon gamma in a T cell-dependent manner. Thus, autophagy promotes tumorigenesis by promoting intrinsic and extrinsic tumor metabolism and by suppressing the ability of the immune system to eliminate tumors. This suggests that autophagy inhibitors may be especially useful for cancer therapy when combined with immunotherapy. To better understand the toxicity of autophagy inhibition to normal tissues, we have examined the functional consequence of conditional Atg7 or Atg5 deletion in adult mice. Whereas Atg7 deletion causes neurodegeneration in 2-3 months, Atg5 deletion causes very specific loss of telocytes and stem cells in the ileum part of the intestine and rapid death due to a more abrupt loss of autophagy function. This indicates that there is a difference in the sensitivity of cell types and tissues to the loss of autophagy and that there are discrete functional dependencies on different ATGs. Citation Format: Eileen P. White. Role of autophagy in cancer metabolism [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA19.