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.

胰腺导管腺癌 (PDAC) 细胞需要大量代谢重新布线以克服营养限制和免疫监视。然而，必需的胰腺肿瘤生长的代谢途径在体内却知之甚少。为了解决这个问题，我们在培养或移植到免疫活性小鼠体内的 PDAC 细胞中进行了以代谢为中心的 CRISPR 筛选。虽然在这些条件下大多数代谢基因的本质出人意料地相似，但一小部分代谢基因对于肿瘤进展是不同的。其中，由于血红素在体内的限制作用，血红素合成的丧失减少了肿瘤的生长，一种独立于组织来源或免疫系统的影响。我们的筛选还将自噬鉴定为胰腺肿瘤免疫逃避的代谢要求。从机制上讲，自噬通过 TNFα 诱导的体外细胞死亡来保护癌细胞免受 CD8+ T 细胞的杀伤。总而言之，该资源提供了由微环境限制和免疫系统引起的代谢依赖性，提名了潜在的抗癌靶点。