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，免疫疗法已成为肿瘤治疗的革命性策略。然而，胰腺导管腺癌（PDAC）是一种免疫学“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要。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) 是以前未被认识到的通过 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 (Treg) 和功能失调的 CD8 ⁺ T 细胞呈正相关。一系列体外和体内实验证明LMO7在促进Treg细胞分化和趋化性同时抑制CD8 ⁺ T细胞和自然杀伤细胞的细胞毒性方面具有显着作用。从机制上来说，LMO7通过其LIM结构域直接结合并促进Foxp1的泛素化和降解。 Foxp1 通过分别与位点 2 和 I/III 结合来负调节转化生长因子-β (TGF-β) 和 CC 基序趋化因子配体 5 (CCL5) 的表达。 TGF-β 和 CCL5 水平升高有助于 Treg 细胞富集，诱导 PDAC 中的免疫逃避。 TGF-β/CCL5 抗体联合治疗以及 LMO7 抑制，有效逆转了 PDAC 的免疫逃避，激活了免疫反应，并延长了小鼠的存活时间。因此，本研究确定 LMO7 是一种通过促进 Treg 细胞富集和抑制细胞毒性效应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。