Intermittent fasting remodels gut ecosystem to influence initiation and therapy responses in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest cancers related-survival rates with high resistance to therapies and no available preventive strategies. Even immunotherapy, which has transformed cancer treatment by providing survival benefits in many solid tumors, has shown limited efficacy in PDAC. Eating patterns can modulate the composition and metabolic activity of the gut microbiota, thereby affecting anti-tumor immune responses. Fasting, a common treatment for pancreatic inflammatory conditions, can affect the composition of gut microbiota, regulates immunity and host metabolic responses. Although fasting is known to offer therapeutic benefits in pancreatic disorders such as pancreatitis and diabetes, its potential role in the prevention or treatment of pancreatic cancer remains unclear. Intermittent fasting (IF) refers to dietary regimens that limit food intake to specific time windows while allowing ad libitum calorie consumption during those periods. Using multiple spontaneous genetically engineered premalignant and orthotopic murine cancer models, we show that IF delays pancreatic tumorigenesis and induces sensitivity to immunotherapy in PDAC. IF-mediated reversal of PD-1 blockade resistance is dependent on gut microbiota mediated CD8 + T cells activation and migration. IF modulates the relative abundance of gut microbiota as well as the serum metabolite levels, which activates intratumoral dendritic cells (DCs). Timeseries single cell transcriptomic analysis revealed that IF remodels the circadian clock of CD8 + T cells and promotes anti-tumor immune responses through shifting the oscillation of genes, including Kat2b , E2f4 , Carns1 and Ccnc . Integration of these gene-expression profiles enables stratification of survival among PDAC patients. Spatial analysis confirmed that long-term fasting was associated with increased the proportion of CD8 + T cells which were in proximity to DCs compared to short-term fasting, suggesting clinical evidence supporting a role for fasting in the redistribution of immune cells within the tumor microenvironment of PDAC. Our findings demonstrate the efficacy of IF in PDAC prevention and reversal of therapy resistance by modulating the activation and egress of rhythmic CD8 + T cells, ultimately affecting the pancreas tumor ecosystem.