Classic versus innovative strategies for immuno-therapy in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a dismal prognosis. Immunotherapy with immune checkpoint inhibitors (ICIs), either as monotherapy, in combination with other ICIs, or alongside chemotherapy, has significantly improved outcomes in several solid tumors. However, its efficacy in PDAC remains limited due to multiple resistance mechanisms. Key determinants of immunotherapy resistance in PDAC include physical barriers that hinder immune cells infiltration, such as aberrant vasculature, cancer-associated fibroblasts (CAFs), and excessive hyaluronic acid deposition in the tumor microenvironment (TME). Additionally, PDAC is characterized by an immunosuppressive TME enriched with regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and by low immunogenicity of tumor cells due to KRAS mutations, MYC overexpression, and a low tumor mutational burden, further impairing antitumor immunity. This review discusses advanced drug delivery systems to overcome determinants of immunotherapy resistance and to improve outcomes, explores emerging immunotherapy strategies, including adoptive cell therapies, cancer vaccines, and the potential role of microbiota as modulator of TME through fecal microbiota transplantation or intratumoral bacterial inoculation. Given the ambivalent role of microbiota in PDAC, the need for a clear definition of favorable strains and their selection is highlighted. Emerging approaches involving engineered bacteria and artificial intelligence applications are also explored. Finally, we propose a hypothetical conceptual framework for an innovative multimodal immunotherapy approach to overcome resistance and improve clinical outcomes in PDAC.