Pancreatic cancer, primarily ductal adenocarcinoma (PDAC), remains a significant cause of cancer-related deaths due to its late detection and resistance to treatment. Current therapies, such as chemotherapy and radiotherapy, offer only marginal improvements in survival. Immunotherapy has emerged as a promising approach, but the tumor's immunosuppressive microenvironment poses significant challenges. This article reviews the immunosuppressive microenvironment of pancreatic cancer and discusses various immunotherapy options, including oncolytic viruses, T-cell receptor (TCR)-engineered and chimeric antigen receptor (CAR) T-cell therapy, CAR natural killer (NK) cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells. It also highlights the role of the gut microbiome and CRISPR/Cas9 gene-editing technology in enhancing immunotherapy responses. Despite progress, major challenges remain, including the tumor's immunosuppressive nature and the need for more effective strategies to overcome these barriers. The article concludes by discussing the future directions and potential solutions for improving the effectiveness of immunotherapy in pancreatic cancer.Pancreatic cancer, primarily ductal adenocarcinoma (PDAC), remains a significant cause of cancer-related deaths due to its late detection and resistance to treatment. Current therapies, such as chemotherapy and radiotherapy, offer only marginal improvements in survival. Immunotherapy has emerged as a promising approach, but the tumor's immunosuppressive microenvironment poses significant challenges. This article reviews the immunosuppressive microenvironment of pancreatic cancer and discusses various immunotherapy options, including oncolytic viruses, T-cell receptor (TCR)-engineered and chimeric antigen receptor (CAR) T-cell therapy, CAR natural killer (NK) cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells. It also highlights the role of the gut microbiome and CRISPR/Cas9 gene-editing technology in enhancing immunotherapy responses. Despite progress, major challenges remain, including the tumor's immunosuppressive nature and the need for more effective strategies to overcome these barriers. The article concludes by discussing the future directions and potential solutions for improving the effectiveness of immunotherapy in pancreatic cancer.