Combination Immunotherapy in Pancreatic Cancer: Current Clinical Evidence and Mechanistic Rationale for Overcoming a “Cold” Tumor

Pancreatic ductal adenocarcinoma (PDAC) resists checkpoint blockades outside uncommon molecularly selected populations. This narrative review relates clinical combination studies to four overlapping resistance mechanisms: deficient antigenicity, presentation and priming; restricted effector-cell access; suppressive myeloid and regulatory-cell programs; and T-cell dysfunction. The grouping is an organizing heuristic, not a validated treatment-selection algorithm. A source audit through 5 September 2026 reconciled a nonexhaustive inventory of 85 supplied study/cohort entries and relevant additional reports; 84 inventory entries remain in the synthesis after the exclusion of 1 trial. Trial design, endpoint success, component attribution and pharmacodynamic evidence were assessed separately. PA.7 and CISPD3 did not improve their primary survival endpoints when checkpoint blockade was added to chemotherapy. Positive or apparently favorable findings require design-specific interpretation: NASCA changed several components, KG4/2015 pooled randomized and nonrandomized controls, and early vaccine signals have not established a routine benefit. POLAR did not meet its co-primary activity criteria; preliminary SWOG S2001 results did not demonstrate benefits from adding pembrolizumab to olaparib. dMMR/MSI-H remains an established tumor-agnostic selection biomarker, while exploratory PA.7 and tissue-state signatures require independent validation. Human immune changes, immunogenicity and target engagement should not be equated with clinical efficacy. Future trials should test defined component contributions, appropriate pharmacodynamic hypotheses and patient-reported outcomes, with sampling adapted to disease setting and feasibility.