Transient Systemic Autophagy Inhibition Is Selectively and Irreversibly Deleterious to Lung Cancer

Autophagy is a conserved catabolic process that maintains cellular homeostasis. Autophagy supports lung tumorigenesis and is a poten-tial therapeutic target in lung cancer. A better understanding of the importance of tumor cell-autonomous versus systemic autophagy in lung cancer could facilitate clinical translation of autophagy inhibition. Here, we exploited inducible expression of Atg5 shRNA to temporally control Atg5 levels and to generate reversible tumor-specific and systemic autophagy loss mouse models of KrasG12D/+/-;p53-/- (KP) non-small cell lung cancer (NSCLC). Transient suppression of sys-temic but not tumor Atg5 expression significantly reduced established KP lung tumor growth without damaging normal tissues. In vivo 13C isotope tracing and metabolic flux analyses demonstrated that sys-temic Atg5 knockdown specifically led to reduced glucose and lactate uptake. As a result, carbon flux from glucose and lactate to major metabolic pathways, including the tricarboxylic acid cycle, glycolysis, and serine biosynthesis, was significantly reduced in KP NSCLC following systemic autophagy loss. Furthermore, systemic Atg5 knockdown increased tumor T-cell infiltration, leading to T-cell -mediated tumor killing. Importantly, intermittent transient system-ic Atg5 knockdown, which resembles what would occur during autophagy inhibition for cancer therapy, significantly prolonged lifespan of KP lung tumor-bearing mice, resulting in recovery of normal tissues but not tumors. Thus, systemic autophagy supports the growth of established lung tumors by promoting immune evasion and sustaining cancer cell metabolism for energy produc-tion and biosynthesis, and the inability of tumors to recover from loss of autophagy provides further proof of concept that inhibition of autophagy is a valid approach to cancer therapy.Significance: Transient loss of systemic autophagy causes irre-versible damage to tumors by suppressing cancer cell metabolism and promoting antitumor immunity, supporting autophagy inhi-bition as a rational strategy for treating lung cancer.