Purpose of Review <p>Despite major advances inimmunotherapy, pancreatic ductal adenocarcinoma (PDAC) remains one of the most immunotherapy-resistant solid tumors. This review aims to summarize the key biological mechanisms underlying immune resistance in PDAC and to evaluate established and emerging biomarkers that may guide immunotherapy strategies.</p> Recent Findings <p>Resistance to immunotherapy in PDAC arises from the interplay of tumor-intrinsic oncogenic signaling, low antigenicity, defective antigen presentation, and a profoundly immunosuppressive tumor microenvironment characterized by dense desmoplasia, hypovascularity, metabolic competition, and enrichment of regulatory T-cells, myeloid-derived suppressor cells, tumor-associated macrophages, and cancer-associated fibroblasts. While MSI-H/dMMR and high tumor mutational burden identify small subsets of patients who may benefit from immune checkpoint blockade, most other biomarkers, including PD-L1 expression, homologous recombination deficiency, KRAS-related immune phenotypes, and circulating markers such as ctDNA and exosomal PD-L1, remain investigational or primarily prognostic. Emerging data highlight the importance of transcriptomic, spatial, and composite biomarker approaches to better capture tumor–immune interactions.</p> Summary <p> PDAC exhibits a complex and actively maintained state of immune resistance that cannot be overcome by checkpoint inhibition alone. Future progress will depend on biomarker-guided combination strategies targeting oncogenic pathways, stromal barriers, and innate immune suppression, along with prospective validation of integrated, multimodal biomarker models to advance precision immuno-oncology in PDAC.</p>