胰腺导管腺癌（PDAC）是最免疫抑制性的肿瘤类型之一。肿瘤免疫微环境（TIME）主要由免疫细胞与异质性肿瘤细胞之间的相互作用驱动。在本研究中，我们旨在调查肿瘤细胞在TIME形成中的机制，并根据基因型异质性为PDAC患者提供潜在的联合治疗策略。 通过高度多重成像质谱细胞测量、RNA测序、时间飞行质谱细胞测量和多重免疫荧光染色，鉴定与PDAC中低免疫激活相关的促肿瘤蛋白。通过体外共培养系统、原位PDAC同种移植瘤模型、流式细胞测量和免疫组织化学等方法来探索蛋白质富含的肠蛋白1（CRIP1）在肿瘤进展和TIME形成中的生物学功能。然后，我们进行了RNA测序、质谱分析和染色质免疫共沉淀，以研究CRIP1的潜在机制。 我们的结果显示，在免疫激活低的PDAC组织中，CRIP1经常上调。高表达的CRIP1诱导髓系衍生抑制性细胞（MDSC）的浸润，并促进免疫抑制的肿瘤微环境。在机制上，我们主要发现CRIP1结合到核因子kappa-B（NF-κB）/p65，并以依赖于进口蛋白的方式促进其核转位，导致CXCL1/5的转录激活。PDAC源性的CXCL1/5促进MDSC的趋化迁移，从而驱动免疫抑制。CXCR1/2的抑制剂SX-682阻断了肿瘤MDSC的招募，并增强了T细胞的活化。抗PD-L1治疗与SX-682的联合治疗在高CRIP1表达的肿瘤小鼠中引发了增加的CD8+T细胞浸润和强效的抗肿瘤活性。 CRIP1/NF-κB/CXCL轴在触发PDAC免疫逃逸和TIME形成中起着关键作用。阻断这一信号通路可防止MDSC的转移，从而使PDAC对免疫疗法敏感化。©作者（或其雇主）2023年。根据CC BY-NC许可进行再利用。不得进行商业再利用。由BMJ出版。

Pancreatic ductal adenocarcinoma (PDAC) is among the most immunosuppressive tumour types. The tumour immune microenvironment (TIME) is largely driven by interactions between immune cells and heterogeneous tumour cells. Here, we aimed to investigate the mechanism of tumour cells in TIME formation and provide potential combination treatment strategies for PDAC patients based on genotypic heterogeneity.Highly multiplexed imaging mass cytometry, RNA sequencing, mass cytometry by time of flight and multiplex immunofluorescence staining were performed to identify the pro-oncogenic proteins associated with low immune activation in PDAC. An in vitro coculture system, an orthotopic PDAC allograft tumour model, flow cytometry and immunohistochemistry were used to explore the biological functions of cysteine-rich intestinal protein 1 (CRIP1) in tumour progression and TIME formation. RNA sequencing, mass spectrometry and chromatin immunoprecipitation were subsequently conducted to investigate the underlying mechanisms of CRIP1.Our results showed that CRIP1 was frequently upregulated in PDAC tissues with low immune activation. Elevated CRIP1 expression induced high levels of myeloid-derived suppressor cell (MDSC) infiltration and fostered an immunosuppressive tumour microenvironment. Mechanistically, we primarily showed that CRIP1 bound to nuclear factor kappa-B (NF-κB)/p65 and facilitated its nuclear translocation in an importin-dependent manner, leading to the transcriptional activation of CXCL1/5. PDAC-derived CXCL1/5 facilitated the chemotactic migration of MDSCs to drive immunosuppression. SX-682, an inhibitor of CXCR1/2, blocked tumour MDSC recruitment and enhanced T-cell activation. The combination of anti-PD-L1 therapy with SX-682 elicited increased CD8+T cell infiltration and potent antitumor activity in tumour-bearing mice with high CRIP1 expression.The CRIP1/NF-κB/CXCL axis is critical for triggering immune evasion and TIME formation in PDAC. Blockade of this signalling pathway prevents MDSC trafficking and thereby sensitises PDAC to immunotherapy.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.