PO.TB10.17 · 肿瘤生物学
调控胰液中ENPP1-STING的交互作用以重塑胰腺癌的肿瘤免疫格局
Modulating pancreatic juice ENPP1-STING crosstalk to reprogram the tumor immune landscape in pancreatic cancer
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作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：
胰腺癌是致死率最高的实体肿瘤之一，主要原因在于其高度免疫抑制的肿瘤微环境（TME），其特征为T细胞浸润不足以及对免疫治疗的耐药。我们此前已证明，通过自噬接头蛋白NBR1和p62调控肝星状细胞中的STING（干扰素基因刺激因子）通路，可将肝细胞癌从“冷”免疫表型转变为“热”免疫表型（Molecular Cell，Nishimura S.，2024）。这些发现凸显了在基质区室内精准调控STING通路的治疗潜力。
目的：
本研究旨在阐明ENPP1（外切核苷酸焦磷酸酶/磷酸二酯酶1）——一种在胰液中高度富集的酶——如何通过调节细胞外cGAMP的可用性及STING激活来塑造胰腺癌的TME。由于ENPP1可降解cGAMP（驱动STING信号传导的关键第二信使），我们假设ENPP1活性升高会抑制固有免疫感知，并促进胰腺癌形成冷TME。
方法：
我们将分析接受胰腺手术患者的胰液及配对的肿瘤组织。将定量检测ENPP1酶活性、cGAMP降解能力以及STING通路激活情况（TBK1/IRF3磷酸化、I型干扰素特征）。将开展免疫谱分析，以评估其与T细胞浸润、髓系构成及免疫排斥标志物之间的相关性。我们将进一步评估ENPP1水平是否与治疗耐药或临床结局相关。
结果与意义：
我们预期高ENPP1活性将与STING信号受抑及免疫浸润减少相关，从而阐明胰腺肿瘤维持免疫学冷TME的一种机制。这项工作有望确立ENPP1作为治疗耐药的生物标志物，并支持开发靶向ENPP1-STING的策略（如抑制ENPP1或稳定cGAMP），以将胰腺肿瘤转变为更具免疫应答性的状态。基于胰液的免疫监测可能为实时评估TME免疫状态提供一种微创工具。
查看英文原文 English abstract
Background:
Pancreatic cancer is among the deadliest solid tumors, primarily due to its profoundly immunosuppressive tumor microenvironment (TME) characterized by poor T-cell infiltration and resistance to immunotherapy. We previously demonstrated that modulation of the STING (Stimulator of Interferon Genes) pathway in hepatic stellate cells, controlled by the autophagy adaptors NBR1 and p62, can convert hepatocellular carcinoma from a “cold” to a “hot” immune phenotype (Molecular Cell, Nishimura S., 2024). These findings highlight the therapeutic potential of precise STING pathway regulation within the stromal compartment.
Objective:
This study aims to elucidate how ENPP1 (ecto-nucleotide pyrophosphatase/phosphodiesterase 1), an enzyme highly enriched in pancreatic juice, shapes the pancreatic TME by modulating extracellular cGAMP availability and STING activation. Because ENPP1 degrades cGAMP-the essential second messenger driving STING signaling-we hypothesize that elevated ENPP1 activity suppresses innate immune sensing and promotes a cold TME in pancreatic cancer.
Methods:
We will analyze pancreatic juice and matched tumor tissues from patients undergoing pancreatic surgery. ENPP1 enzymatic activity, cGAMP degradation capacity, and STING pathway activation (TBK1/IRF3 phosphorylation, type I interferon signatures) will be quantified. Immune profiling will be performed to assess correlations with T-cell infiltration, myeloid composition, and markers of immune exclusion. We will further evaluate whether ENPP1 levels are associated with treatment resistance or clinical outcomes.
Results and Significance:
We anticipate that high ENPP1 activity will correlate with suppressed STING signaling and reduced immune infiltration, defining a mechanism by which pancreatic tumors maintain an immunologically cold TME. This work has the potential to establish ENPP1 as a biomarker for therapeutic resistance and to support the development of ENPP1-STING-targeted strategies-such as ENPP1 inhibition or cGAMP stabilization-to convert pancreatic tumors into a more immune-responsive state. Pancreatic juice-based immune monitoring may provide a minimally invasive tool for real-time assessment of TME immune status.
利益披露 Disclosure
S. Nishimura, None..
J. Tauchi, None..
R. Tanaka, None..
S. Kurihara, None..
M. Kinoshita, None..
K. Nishio, None..
H. Shinkawa, None..
T. Ishizawa, None.