With advancements in genomics and immunology, immunotherapy has emerged as a revolutionary strategy for tumor treatment. However, pancreatic ductal adenocarcinoma (PDAC), an immunologically “cold” tumor, exhibits limited responsiveness to immunotherapy. This study aimed to address the urgent need to uncover PDAC’s immune microenvironment heterogeneity and identify the molecular mechanisms driving immune evasion. Using single-cell RNA sequencing datasets and spatial proteomics, we discovered LIM domain only 7 (LMO7) in PDAC cells as a previously unrecognized driver of immune evasion through Treg cell enrichment. LMO7 was positively correlated with infiltrating regulatory T cells (Tregs) and dysfunctional CD8⁺ T cells. A series of in vitro and in vivo experiments demonstrated LMO7’s significant role in promoting Treg cell differentiation and chemotaxis while inhibiting CD8⁺ T cells and natural killer cell cytotoxicity. Mechanistically, LMO7, through its LIM domain, directly bound and promoted the ubiquitination and degradation of Foxp1. Foxp1 negatively regulated transforming growth factor-beta (TGF-β) and C-C motif chemokine ligand 5 (CCL5) expression by binding to sites 2 and I/III, respectively. Elevated TGF-β and CCL5 levels contribute to Treg cell enrichment, inducing immune evasion in PDAC. Combined treatment with TGF-β/CCL5 antibodies, along with LMO7 inhibition, effectively reversed immune evasion in PDAC, activated the immune response, and prolonged mouse survival. Therefore, this study identified LMO7 as a novel facilitator in driving immune evasion by promoting Treg cell enrichment and inhibiting cytotoxic effector functions. Targeting the LMO7-Foxp1-TGF-β/CCL5 axis holds promise as a therapeutic strategy for PDAC.

随着基因组学和免疫学的进步，免疫疗法已成为一种革命性的肿瘤治疗策略。然而，胰腺导管腺癌 （PDAC） 是一种免疫学上的“冷”肿瘤，对免疫治疗的反应有限。本研究旨在解决揭示 PDAC 免疫微环境异质性并确定驱动免疫逃避的分子机制的迫切需求。使用单细胞 RNA 测序数据集和空间蛋白质组学，我们发现 PDAC 细胞中的 LIM 结构域仅 7 （LMO7） 是以前未识别的通过 Treg 细胞富集进行免疫逃避的驱动因素。LMO7 与浸润调节性 T 细胞 （Tregs） 和功能失调的 CD8⁺ T 细胞呈正相关。一系列体外和体内实验表明，LMO7 在促进 Treg 细胞分化和趋化性方面发挥重要作用，同时抑制 CD8⁺ T 细胞和自然杀伤细胞细胞毒性。从机制上讲，LMO7 通过其 LIM 结构域直接结合并促进了 Foxp1 的泛素化和降解。Foxp1 通过分别结合位点 2 和 I/III 负调控转化生长因子-β （TGF-β） 和 C-C 基序趋化因子配体 5 （CCL5） 的表达。TGF-β 和 CCL5 水平升高导致 Treg 细胞富集，诱导 PDAC 中的免疫逃避。TGF-β/CCL5 抗体联合 LMO7 抑制治疗，有效逆转 PDAC 中的免疫逃避，激活免疫反应，延长小鼠存活。因此，本研究确定 LMO7 是通过促进 Treg 细胞富集和抑制细胞毒性效应器功能来驱动免疫逃避的新型促进剂。靶向 LMO7-Foxp1-TGF-β/CCL5 轴有望成为 PDAC 的治疗策略。