Low-dose chemotherapy remodels hepatic immune landscape and potentiates antitumor response to immune checkpoint blockade in cholangiocarcinoma

BACKGROUND AND AIMS: While gemcitabine/cisplatin (GC) combined with anti-PD-L1 is a first-line regimen for advanced intrahepatic cholangiocarcinoma (ICC), efficacy remains limited and toxicity significant, highlighting the need to optimize the therapeutic strategy. We sought to investigate whether low-dose GC (LDGC) could unleash anti-PD-L1-mediated antitumor immunity along with reduced toxicity. APPROACH AND RESULTS: Multiple preclinical ICC mouse models were used to assess the antitumor efficacy and toxicity of LDGC combined with anti-PD-L1. Mechanisms were investigated via single-cell RNA sequencing, flow cytometry, and in vivo/vitro functional assays. Clinical correlation was evaluated in patient-derived tumor fragments and a pilot clinical trial in ICC patients. LDGC combined with anti-PD-L1 treatment efficiently improved tumor immune microenvironment (TIME) through reducing immunosuppressive SPP1 + tumor-associated macrophages (TAMs) while promoting CD8 + T-cell infiltration and cytotoxicity. LDGC reprograms the interplay between STAT1 and STAT3 transcriptional pathways in TAMs, thereby reducing SPP1 expression and weakening the inhibitory effect of the SPP1-VLA-4 signaling axis on CD8 + T cells, ultimately enhancing T-cell cytotoxicity and sensitizing antitumor response to anti-PD-L1. Furthermore, the ICC patients exhibited superior response and tolerance to LDGC combined with immunotherapy. CONCLUSIONS: This study highlights that LDGC remodels the immunosuppressive microenvironment and potentiates anti-PD-L1 therapy, providing a rational regimen for ICC.