胃癌（GC）仍然是一个重大的全球健康挑战，其预后较差，部分原因是其逃避免疫系统的能力。细胞外基质（ECM），特别是胶原蛋白，在肿瘤免疫逃避中发挥着至关重要的作用，但其潜在机制尚不完全清楚。本研究探讨胶原ECM通过激活IL4I1-AHR信号通路促进胃癌免疫逃避的作用。我们在3D胶原凝胶中培养胃癌细胞，并通过与HER2特异性CAR-T共培养来评估其免疫逃避能力细胞。分析IL4I1及其代谢物的表达，并探讨整合素αvβ1在介导胶原蛋白作用中的作用。此外，在体外和体内评估了 IL4I1 诱导的 AHR 激活对 CAR-T 细胞耗竭的影响。我们发现，在胶原蛋白上培养的胃癌细胞表现出对 CAR-T 细胞毒性的抵抗力增强，这与上调相关CAR-T 细胞上的免疫检查点分子和下调的效应细胞因子。这与 IL4I1 表达增加有关，而 IL4I1 表达增加是由 3D 胶原蛋白环境中的整合素 αvβ1 信号进一步诱导的。 IL4I1 代谢物，特别是 KynA，通过激活 AHR 通路促进 CAR-T 细胞耗竭，从而降低细胞毒性和肿瘤生长抑制。我们的研究揭示了胶原 ECM 通过激活 IL4I1- 促进胃癌免疫逃避的新机制AHR 信号传导，导致 CAR-T 细胞耗竭。针对这一通路可能会增强 CAR-T 细胞疗法治疗胃癌的疗效。版权所有 © 2024。由 Elsevier Inc. 出版。

Gastric cancer (GC) remains a significant global health challenge with poor prognosis, partly due to its ability to evade the immune system. The extracellular matrix (ECM), particularly collagen, plays a crucial role in tumor immune evasion, but the underlying mechanisms are not fully understood. This study investigates the role of collagen ECM in promoting immune evasion in gastric cancer by activating the IL4I1-AHR signaling pathway.We cultured gastric cancer cells in 3D collagen gels and assessed their immune evasion capabilities by co-culturing with HER2-specific CAR-T cells. The expression of IL4I1 and its metabolites was analyzed, and the role of integrin αvβ1 in mediating the effects of collagen was explored. Additionally, the impact of IL4I1-induced AHR activation on CAR-T cell exhaustion was evaluated, both in vitro and in vivo.We found that gastric cancer cells cultured on collagen exhibited increased resistance to CAR-T cell cytotoxicity, which was associated with upregulated immune checkpoint molecules and downregulated effector cytokines on CAR-T cells. This was linked to increased IL4I1 expression, which was further induced by integrin αvβ1 signaling within the 3D collagen environment. IL4I1 metabolites, particularly KynA, promoted CAR-T cell exhaustion by activating the AHR pathway, leading to decreased cytotoxicity and tumor growth inhibition.Our study reveals a novel mechanism by which the collagen ECM facilitates immune evasion in gastric cancer through the activation of IL4I1-AHR signaling, contributing to CAR-T cell exhaustion. Targeting this pathway could potentially enhance the efficacy of CAR-T cell therapy in gastric cancer.Copyright © 2024. Published by Elsevier Inc.