Haoqiang Ying1,2, Alec C. Kimmelman3,4, Nabeel Bardeesy5,6, Raghu Kalluri2,7,8,9, Anirban Maitra2,10,11,12 and Ronald A. DePinho2,7 1Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 2Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, University of Texas Health Science Center, Houston, Texas 77030, USA; 3Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, New York 10016, USA; 4Department of Radiation Oncology, New York University Grossman School of Medicine, New York, New York 10016, USA; 5Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA; 6The Cancer Program, Broad Institute, Cambridge, Massachusetts 02142, USA; 7Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 8Department of Bioengineering, Rice University, Houston, Texas 77030, USA; 9Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA; 10Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 11Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 12Sheikh Ahmed Pancreatic Cancer Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA Corresponding authors: rdepinhomdanderson.org, hyingmdanderson.org Abstract

Pancreatic ductal adenocarcinoma (PDAC) poses a grim prognosis for patients. Recent multidisciplinary research efforts have provided critical insights into its genetics and tumor biology, creating the foundation for rational development of targeted and immune therapies. Here, we review the PDAC genomic landscape and the role of specific oncogenic events in tumor initiation and progression, as well as their contributions to shaping its tumor biology. We further summarize and synthesize breakthroughs in single-cell and metabolic profiling technologies that have illuminated the complex cellular composition and heterotypic interactions of the PDAC tumor microenvironment, with an emphasis on metabolic cross-talk across cancer and stromal cells that sustains anabolic growth and suppresses tumor immunity. These conceptual advances have generated novel immunotherapy regimens, particularly cancer vaccines, which are now in clinical testing. We also highlight the advent of KRAS targeted therapy, a milestone advance that has transformed treatment paradigms and offers a platform for combined immunotherapy and targeted strategies. This review provides a perspective summarizing current scientific and therapeutic challenges as well as practice-changing opportunities for the PDAC field at this major inflection point.