Efficacy and Safety of Immune Checkpoint Inhibitors-based Therapy in Patients with High Microsatellite Instability/Mismatch Repair–Deficient Advanced Cholangiocarcinoma: A Propensity Score–Matched Study

Background Microsatelliteinstability-high/mismatch repair-deficient (MSI-H/dMMR) cholangiocarcinoma (CCA) represents a rare molecular subtype with potential sensitivity to immune checkpoint inhibitors (ICIs).However, real-world evidence regarding the efficacy and safety of ICIs in MSI-H/dMMR CCA remains limited. MethodsWe conducted a single-center, retrospective real-world study of patients with advanced CCA treated with ICIs-based regimens.MSI-H/dMMR status was determined by next-generation sequencing and/or immunohistochemistry.A contemporaneous microsatellite-stable (MSS) cohort was included as a control group.Propensity score matching (PSM) was performed to balance baseline characteristics.The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety.Results Among 331 patients, 23 (6.9%) were identified as MSI-H/dMMR.After 1:3 PSM, 23 MSI-H/dMMR patients were matched with 69 MSS/pMMR patients, achieving well-balanced baseline characteristics.MSI-H/dMMR patients demonstrated significantly prolonged survival compared with MSS/pMMR patients.Median PFS was 64.1 months versus 7.2 months, and median OS was 70.5 months versus 14.0 months, respectively (both P<0.001).MSI-H/dMMR status remained the strongest independent prognostic factor for both OS and PFS in multivariable Cox analyses.ORR and DCR were significantly higher in MSI-H patients than in matched MSS/pMMR patients.Subgroup analyses showed consistent survival benefits of MSI-H/dMMR across tumor subtype, PD-L1 expression, and CA19-9 strata.Genomic profiling revealed frequent alterations in ARID1A, PBRM1, and KMT2D among MSI-H/dMMR tumors.ICIs-based therapy was generally well tolerated; grade 3-4 adverse events occurred predominantly in chemotherapy-containing regimens. ConclusionsIn this real-world propensity score-matched study, MSI-H/dMMR CCA was associated with markedly improved survival and durable clinical benefit from ICIs-based therapy, with a manageable safety profile.These findings support MSI-H/dMMR as a key actionable biomarker and underscore the importance of routine MSI testing in CCA.