Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma: from Tumor Biology to Biomarker-Guided Strategies.

Abstract

Purpose of review: 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.

Recent findings: 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. 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.