Immune Evasion in Pancreatic Ductal Adenocarcinoma: Mechanistic Insights and Emerging Strategies to Reinvigorate Anti-Cancer Immunity

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most hard to treat malignancies, characterised by significant immune evasion and resistance to current systemic agents. Despite substantial progress in understanding tumour immunology across other cancer types, PDAC continues to exemplify an immunologically “cold” tumour, where a desmoplastic stroma, inadequate T-cell infiltration, and complex immunosuppressive networks combine to impede effective anti-cancer immunity. This review summarises current knowledge on the mechanisms underlying immune escape in PDAC, including aberrant antigen presentation, stromal–immune crosstalk, recruitment of regulatory T cells and myeloid-derived suppressor cells, and the metabolic and hypoxic constraints imposed by the tumour microenvironment. We also discuss recent advances in preclinical and clinical studies aiming to overcome these barriers, ranging from stromal modulation and targeting immune checkpoints to integrating radiotherapy, chemotherapy, and DNA damage response modulation to enhance immunogenicity. Special emphasis is placed on the emerging concept of therapeutic replication stress and its potential to induce immunogenic cell death and reshape the tumour immune landscape. We outline the mechanistic basis for treatment resistance of PDAC and discuss strategies to convert the malignancy from an immune-resistant to an immune-responsive state.