在免疫治疗时代，初始受益者中的亚优响应率和获得性耐药的发展在包括胃癌在内的多种恶性肿瘤中仍然存在显著挑战。考虑到肿瘤基质，尤其是癌相关成纤维细胞（CAFs）与免疫细胞和肿瘤细胞的相互作用在肿瘤的进展、肿瘤微环境的重塑和治疗反应性方面起着不可或缺的作用，对CAFs的作用以及其功能的关键介体进行深入探索可能为提高当前免疫治疗药物的有效性并进一步实现协同抗肿瘤反应提供新线索。在这里，通过规范生物标记物的共识聚类，对包含来自11个独立数据集的2148例GC患者的四个综合性大规模队列进行了虚拟显微切割，研究发现根据CAFs的丰度可将GC分为三个亚型。通过广泛的免疫基因组分析发现，CAF浸润高的肿瘤表现出不利的预后、恶性表型、较低的肿瘤免疫原性、免疫逃逸的高风险，从而导致免疫治疗的耐药性。通过大规模的单细胞转录组学分析，鉴定出一系列CAF分泌的蛋白质，其中SERPINE2在GC组织的纤维母细胞中受限且通过生物信息学计算和组织芯片分析被证实有助于促进肿瘤微环境以及形成免疫抑制性环境。此外，全癌种调查还证实了SERPINE2在包括各种胃肠恶性肿瘤中的免疫学作用，多个实际免疫治疗队列进一步证实了其对预测免疫治疗效果的意义。总之，这些发现表明CAF来源的SERPINE2是一个具有治疗意义的免疫肿瘤靶点，可进一步协同免疫治疗组合。 版权所有 ©2023 Elsevier Ltd.。

In the era of immunotherapy, the suboptimal response rate and the development of acquired resistance among the initial beneficiaries continue to present significant challenges across multiple malignancies, including gastric cancer (GC). Considering that the interactions of tumor stroma, especially the cancer-associated fibroblasts (CAFs), with immune and tumor cells, play indispensable roles in tumor progression, tumor microenvironment remodeling and therapeutic responsiveness, in-depth exploration on the roles of CAFs and pivotal mediators of their functions may provide novel clues to increase the effectiveness of current immunotherapeutic drugs and further achieve synergistic antitumor response. Herein, through the consensus clustering of canonical biomarkers, three GC subclasses with different abundance of CAFs were virtually microdissected in four integrated bulk cohorts encompassing 2148 GC patients from 11 independent datasets. An extensive immunogenomic analysis revealed that tumors with high CAFs infiltration were characterized with unfavorable outcomes, aggressive phenotypes, decreased tumor immunogenicity, high risk of immune evasion and thus immunotherapeutic resistance. By leveraging large-scale single-cell transcriptomic profiling, a series of CAF-secreted proteins were identified, among which the SERPINE2 was confirmed to be restrictively enriched in stromal fibroblasts of GC tissues and contribute to promoting a protumor milieu and fostering an immunosuppressive microenvironment via bioinformatics computations and tissue microarray analysis. Moreover, pan-cancer investigations generalized the immunological roles of SERPINE2, especially in pan-gastrointestinal malignancies, with multiple real-world immunotherapy cohorts further confirming its implications on predicting immunotherapeutic efficacy. In conclusion, these findings suggest that the CAF-derived SERPINE2 is a promising immune-oncology target with therapeutic implications to further synergize the immunotherapeutic combinations.Copyright © 2023 Elsevier Ltd. All rights reserved.