{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T01:31:34Z","timestamp":1793496694404,"version":"4.5.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Gemcitabine-cisplatin chemotherapy combined with anti-PD-L1 (GCP) therapy exhibits potent antitumor efficacy in patients with advanced intrahepatic cholangiocarcinoma (ICC). We aim to determine the intra-tumoral changes of ICC following GCP therapy in this study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed single-cell RNA-seq (scRNA-seq) of 15 samples from 3 ICC patients receiving GCP therapy. The major findings of scRNA-seq analyses were further validated via analyzing the bulk RNA-seq data from the FU-iCCA cohort (n=244), as well as performing immunohistochemistry (IHC) and multiplex immunofluorescence (mIF) staining on a treatment-na\u00efve tissue microarray (TMA) cohort (n=89) and a GCP-treated cohort (n=32).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      For the scRNA-seq cohort, two patients achieved tumor regression and underwent liver resection after GCP combination therapy. The intra-tumoral enrichment of CCL18\n                      <jats:sup>+<\/jats:sup>\n                      macrophages correlated with poor prognosis of ICC patients after curative resection in the TMA cohort. Reduced fractions of CCL18\n                      <jats:sup>+<\/jats:sup>\n                      and SPP1\n                      <jats:sup>+<\/jats:sup>\n                      macrophages were observed in the GCP-treated ICC specimens which achieved pathological response. Our scRNA-seq analyses revealed significant alterations in the tumor microenvironment following GCP therapy: tumor-infiltrating macrophages underwent a distinct antitumor phenotypic shift, transitioning from M2 toward M1 polarization; concurrently, CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells exhibited enhanced costimulatory signaling characterized by CD81 upregulation and malignant cells demonstrated diminished immune escape characteristics alongside heightened activity in immune response-related pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our preliminary findings reveal a generally reactivated antitumor immune response in ICC following GCP therapy, which could partly illuminate the enigmatic black box of intra-tumoral cellular states associated with treatment response.<\/jats:p>\n                  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