PD-1 blockade plus gemcitabine and nab-paclitaxel in lymph node-dominant metastatic gallbladder cancer: a real-world study and exploratory single-cell analysis

Despite the poor prognosis of distant metastatic gallbladder cancer (mGBC), immunotherapy has emerged as a promising therapeutic approach. In this retrospective case series, we report the clinical outcomes of PD‑1 blockade combined with gemcitabine and nab‑paclitaxel (PD‑1 and AG) in patients with mGBC and distant lymph-node metastases (LN + mGBC). An exploratory four-type classification based on primary tumor extent, tumor burden distribution, and metastatic pattern was proposed. To provide exploratory population-level corroboration of the prognostic discrimination of this classification, we queried the Surveillance, Epidemiology, and End Results (SEER) database. In this real-world study, we reported and analyzed clinical and survival data from 11 patients with lymph-node-dominant mGBC treated with PD-1 blockade (e.g., pembrolizumab) plus gemcitabine and nab-paclitaxel (PD-1 and AG) between 2020 and 2025. An independent, exploratory single-cell transcriptomic analysis of a separate cohort of patients with resectable GBC ( n = 12) was performed to characterize the immune microenvironment in LN+ GBC and to provide a general rationale for checkpoint targeting in LN+ disease. Median follow-up was 26.8 months. Median OS was not reached, and the 12-month OS rate was 100%. Median PFS was 23.7 months. Objective responses were observed in all 11 patients based on the best radiographic response per RECIST version 1.1, including radiographic complete responses (CR) in six patients. All patients who underwent conversion surgery with R0 resection achieved no evidence of disease (NED) postoperatively. Grade 3–4 adverse events (AEs) occurred in 7 of 11 patients. In the independent exploratory single-cell transcriptomic analysis, we characterized the cellular composition and cell–cell communication of tumor-infiltrating cells. Greater infiltration of exhausted CD8+ T cells and a more immunologically active microenvironment were observed in LN+ mGBC. PD-1 and AG was associated with durable responses in patients with gallbladder cancer and lymph-node-dominant metastases. Given the small, uncontrolled, retrospective design and potential selection bias, conclusions regarding efficacy remain limited. Prospective controlled studies with integrated biospecimen collection are needed for definitive evaluation. This was a multicenter retrospective study conducted at two high-volume hepatobiliary centers in China: Renji Hospital of Shanghai Jiao Tong University School of Medicine and Zhongshan Hospital Affiliated to Fudan University. Ethical approval for this study was conducted by the ethics committee of the research department at Renji Hospital, Shanghai Jiao Tong University School of Medicine (KY2021-175-B) and registered in the Chinese Clinical Trial Registry (ChiCTR2200065916).