A STING signaling relay from tumor cells to macrophages mediates the improved efficacy of combination chemotherapy in pancreatic cancer.

BACKGROUND: The therapeutic efficacy of traditional chemotherapy on pancreatic ductal adenocarcinoma (PDAC) remains dismal. In this study, we investigated the efficacy of adding cisplatin to the standard first-line gemcitabine plus nab-paclitaxel (AG) regimen (referred to as AGP) for PDAC treatment, and elucidated the underlying mechanisms, particularly the role of the cGAS-STING pathway in mediating chemotherapy-induced antitumor immunity in PDAC. METHODS: We first reported the therapeutic efficacy of an AGP regimen in patients with PDAC through a clinical retrospective analysis. Next, we mimicked the enhanced efficacy of the AGP regimen in both subcutaneous and orthotopic PDAC mouse models. Comprehensive immune profiling was performed using mass cytometry, flow cytometry, multiplex immunofluorescence, and RNA sequencing to characterize changes in immune cell populations and phenotypes. The functional significance of the cGAS-STING pathway was investigated through genetic ablation of tumor cells and macrophages. Tumor-macrophage interactions were further explored via co-culture assays. Clinical relevance was assessed through a retrospective analysis of cohorts of patients with PDAC and immunohistochemical evaluation of STING expression in tumor tissues. RESULTS: The AGP regimen confers promising potential to AG regimen in patients with PDAC as well as in PDAC mouse models. Mechanistically, cisplatin-induced DNA damage in tumor cells activated the tumor-intrinsic cGAS-STING pathway, which facilitated the recruitment and activation of CD8(+) T cells. Furthermore, phagocytosis of tumor-derived damage-associated molecular patterns by tumor-associated macrophages (TAMs) triggered the activation of cGAS-STING signaling and promoted M1 polarization of TAMs without obvious macrophage cell death. Such "STING signaling relay" between tumor cells and TAMs reprogrammed the tumor microenvironment and facilitated chemotherapy efficacy. Clinically, high STING expression in PDAC tissues was associated with increased infiltration of cytotoxic T cells and M1-like macrophages, and was identified as an independent predictor of improved patient prognosis. CONCLUSIONS: This study reports AGP regimen as a promising therapeutic modality for PDAC, and provides a detailed mechanism by which a STING-mediated signaling relay from PDAC tumor cells to TAMs boost antitumor immunity and contribute to AGP chemotherapy efficacy. Furthermore, STING expression in tumor tissues correlated with improved prognosis, highlighting its potential as a predictive biomarker and promising therapeutic target.