Pancreatic ductal adenocarcinoma (PDAC) is a significant contributor to cancer-related morbidity and mortality, and it is known for its resistance to conventional treatment regimens, including chemotherapy and immune checkpoint blockade (ICB)-based therapies. We have previously shown that Urolithin A (Uro A), a gut microbial metabolite derived from pomegranates, can target and inhibit KRAS-dependent PI3K/AKT/mTOR signaling pathways to overcome therapeutic resistance and improve survival in PDAC. However, the effect of Uro A on the tumor immune microenvironment and its ability to enhance ICB efficacy has not been explored. This study demonstrates that Uro A treatment reduces stromal fibrosis and reinvigorates the adaptive T-cell immune response to overcome resistance to PD-1 blockade in a genetically engineered mouse model (GEMM) of PDAC. Flow cytometric-based analysis of Uro A-treated mouse tumors revealed a significant attenuation of immunosuppressive tumor-associated M2-like macrophages with a concurrent increase in the infiltration of CD4+ and CD8+ T cells with memory-like phenotype along with reduced expression of the exhaustion-associated protein, PD-1. Importantly, the combination of Uro A treatment with anti-PD-1 immunotherapy promoted enhancement of the antitumor response with increased infiltration of CD4+ Th1 cells, ultimately resulting in a remarkable improvement in overall survival in GEMM of PDAC. Overall, our findings provide preclinical evidence for the potential of Uro A as a novel therapeutic agent to increase sensitivity to immunotherapy in PDAC and warrant further mechanistic exploration in preclinical and clinical studies. Significance:Immunotherapeutic agents are ineffective against pancreatic cancer, mainly due to the immunosuppressive tumor microenvironment and stromal desmoplasia. Our current study demonstrates the therapeutic utility of a novel gut microbial metabolite, Uro A, to remodel the stromal-immune microenvironment and improve overall survival with anti-PD-1 therapy in pancreatic cancer.

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乐备实（上海优宁维生物科技股份有限公司旗下全资子公司），是国内专注于提供高质量蛋白检测以及组学分析服务的实验服务专家，自2018年成立以来，乐备实不断寻求突破，公司的服务技术平台已扩展到单细胞测序、空间多组学、流式检测、超敏电化学发光、Luminex多因子检测、抗体芯片、PCR Array、ELISA、Elispot、PLA蛋白互作、多色免疫组化、DSP空间多组学等30多个，建立起了一套涵盖基因、蛋白、细胞以及组织水平实验的完整检测体系。

 
我们可提供从样本运输、储存管理、样本制备、样本检测到检测数据分析的全流程服务。凭借严格的实验室管理流程、标准化实验室操作、原始数据储存体系以及实验项目管理系统，已经为超过3000家客户单位提供服务，年检测样本超过100万，受到了广大客户的信任与支持。