Targeting the metabolism and immune system in pancreatic ductal adenocarcinoma: Insights and future directions

• Published in: Cytokine & growth factor reviews 2023-06, Vol.71-72, p.26-39
• Main Authors: Bandi, Dhana Sekhar Reddy, Sarvesh, Sujith, Farran, Batoul, Nagaraju, Ganji Purnachandra, El-Rayes, Bassel F.
• Format: Article
• Language: English
• Subjects: Immunometabolism; Immunotherapy; Metabolic pathways; Pancreatic ductal adenocarcinoma; Tumor microenvironment
• ISSN: 1359-6101
• DOI: 10.1016/j.cytogfr.2023.06.006

Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), presents a challenging landscape due to its complex nature and the highly immunosuppressive tumor microenvironment (TME). This immunosuppression severely limits the effectiveness of immune-based therapies. Studies have revealed the critical role of immunometabolism in shaping the TME and influencing PDAC progression. Genetic alterations, lysosomal dysfunction, gut microbiome dysbiosis, and altered metabolic pathways have been shown to modulate immunometabolism in PDAC. These metabolic alterations can significantly impact immune cell functions, including T-cells, myeloid-derived suppressor cells (MDSCs), and macrophages, evading anti-tumor immunity. Advances in immunotherapy offer promising avenues for overcoming immunosuppressive TME and enhancing patient outcomes. This review highlights the challenges and opportunities for future research in this evolving field. By exploring the connections between immunometabolism, genetic alterations, and the microbiome in PDAC, it is possible to tailor novel approaches capable of improving immunotherapy outcomes and addressing the limitations posed by immunosuppressive TME. Ultimately, these insights may pave the way for improved treatment options and better outcomes for PDAC patients. [Display omitted] •The interaction of pancreatic ductal adenocarcinoma (PDAC) and the immune system is critical in shaping the immunometabolic landscape.•Tumor-associated macrophages (TAMs) are known to undergo metabolic reprogramming to exist in the nutrient-depleted tumor microenvironment (TME) and contribute to PDAC progression.•PDAC cells undergo metabolic reprogramming to meet high energy demands by using immune modulators in the TME, including glucose, amino acid, and lipid metabolism, to facilitate their proliferation and survival.•Targeting the immunometabolic interactions of PDAC cells by combining metabolic inhibitors with immune modulators is a possible strategy for PDAC therapy.