Selectively eliminating senescent cancer-associated fibroblasts via chidamide and chemo-immunotherapy in metastatic pancreatic cancer: phase 2 clinical trial results (PANDA-1706)

Lymph node metastasis (LNM) in early-stage pancreatic ductal adenocarcinoma (PDAC) predicts systemic dissemination and poor survival, yet its underlying mechanisms remain elusive. Here, we demonstrate that senescent cancer-associated fibroblasts (senCAFs) drive lymphatic remodeling and LNM in early-stage PDAC and predict distant metastasis. Genetic or pharmacologic elimination of senCAFs suppresses LNM and distant metastasis. Mechanistically, senCAFs promote lymphangiogenesis and LNM by augmenting glucose metabolism and lactate production, which activates lactylation-mediated serine metabolism to protect lymphatic endothelial cells from oxidative stress. Moreover, using advanced multiplex imaging techniques, we have discovered that CCR4 + Tregs from the draining lymph nodes accumulated around lymphatic vessels. This localized accumulation is facilitated by lymphatic endothelia enriched in senCAFs, which established an immunosuppressive peri-lymphatic niche. Furthermore, high throughput drug screening platform determines selective clearance of senCAFs via chidamide, one HDAC inhibitor, attenuates tumor progression and improves chemo-immunotherapeutic efficacy at low concentrations. We subsequently initiated a phase 2 clinical trial in metastatic PDAC patients. Here we report the results of the chidamide arm (chidamide and nab-paclitaxel/gemcitabine plus anti-PD-1/CTLA-4). The pre-specified primary endpoint of this arm was met, with a confirmed objective response rate. Collectively, these findings reveal a closed link between cellular senescence, metabolic reprograming, spatial immusuppressive niche and PDAC metastasis, offering the potential senolytic means to improve chemo-immunotherapy efficacy in PDAC patients. Clinical Trials.gov. identifier: NCT06951997.