Tumor–stromal metabolic crosstalk in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a dire prognosis. Standard-of-care chemotherapy regimens offer marginal survival benefit and carry risk of severe toxicity, while immunotherapy approaches have uniformly failed in clinical trials. Extensive desmoplasia in the PDAC tumor microenvironment (TME) disrupts blood flow to and from the tumor, thereby creating a nutrient-depleted, hypoxic, and acidic milieu that suppresses the function of antitumor immune cells and imparts chemotherapy resistance. Additionally, recent seminal studies have demonstrated crucial roles for metabolic crosstalk - the exchange of metabolites between PDAC cells and stromal cell populations in the TME - in establishing and maintaining core malignant behaviors of PDAC: tumor growth, metastasis, immune evasion, and therapy resistance. In this review, we provide a conceptual overview of metabolic crosstalk and how it evolves under various selection pressures in the TME, analyze the landscape of proposed tumorigenic metabolic crosstalk pathways, and highlight potentially druggable nodes.