Pancreatic ductal adenocarcinoma (PDAC) cells require substantial metabolic rewiring to overcome nutrient limitations and immune surveillance. However, the metabolic pathways necessary for pancreatic tumor growth in vivo are poorly understood. To address this, we performed metabolism-focused CRISPR screens in PDAC cells grown in culture or engrafted in immunocompetent mice. While most metabolic gene essentialities are unexpectedly similar under these conditions, a small fraction of metabolic genes are differentially required for tumor progression. Among these, loss of heme synthesis reduces tumor growth due to a limiting role of heme in vivo, an effect independent of tissue origin or immune system. Our screens also identify autophagy as a metabolic requirement for pancreatic tumor immune evasion. Mechanistically, autophagy protects cancer cells from CD8+ T cell killing through TNFα-induced cell death in vitro. Altogether, this resource provides metabolic dependencies arising from microenvironmental limitations and the immune system, nominating potential anti-cancer targets. Display omitted •CRISPR screens identify metabolic genes essential for pancreatic tumor growth•Most metabolic essentialities are similar in cells grown in culture and as tumors•Heme synthesis is limiting due to increased heme degradation in the tumor environment•Autophagy enables cancer cells to evade CD8+ T cell killing Using in vivo CRISPR screens, Zhu et al. map metabolic genes essential for pancreatic cancer cells to grow in culture and as tumors. While most essentialities are similar under these conditions, genetic screens identify heme synthesis and autophagy as metabolic requirements specific to the tumor environment.