我们之前的研究定义了一种新型代谢癌相关成纤维细胞亚群(meCAFs)，其丰富在松散型胰腺导管腺癌（PDAC）中，并且与CD8+ T细胞的积累相关。一致的是，meCAFs的丰度与PDAC患者的预后不良但免疫治疗反应更佳相关。然而，meCAFs的代谢特性及其与CD8+ T细胞的相互作用尚需阐明。在本研究中，我们确定了PLA2G2A作为meCAFs的一个标记。特别是，PLA2G2A+ meCAFs的丰度与总CD8+ T细胞的积累有正相关关系，与PDAC患者的临床预后和内肿瘤CD8+ T细胞浸润呈负相关。我们证明了PLA2G2A+ meCAFs显著削弱了肿瘤浸润CD8+ T细胞的抗肿瘤能力，并促进了PDAC中的肿瘤免疫逃逸。在机制上，PLA2G2A通过MAPK/Erk和NF-κB信号通路作为关键可溶性介质调节CD8+ T细胞的功能。总之，我们的研究确定了PLA2G2A+ meCAFs在促进肿瘤免疫逃逸中的未被认识的作用，通过阻碍CD8+ T细胞的抗肿瘤免疫功能，强烈建议PLA2G2A作为PDAC免疫治疗的有前途的生物标志物和治疗靶点。版权所有 © 2023 The Authors。由Elsevier B.V.出版。保留所有权利。

Our previous research defined a novel metabolic cancer associated fibroblasts subset (meCAFs) enriched in loose-type pancreatic ductal adenocarcinoma (PDAC) and related to CD8+ T cells accumulation. Consistently, the abundance of meCAFs was associated with poor prognosis but better immunotherapy responses in PDAC patients. However, the metabolic characteristic of meCAFs and its cross-talk with CD8+ T cells remain to be elucidated. In this study, we identified PLA2G2A as a marker of meCAFs. In particular, the abundance of PLA2G2A+ meCAFs was positively related to the accumulation of total CD8+ T cells and negatively correlated with clinical outcomes of PDAC patients and infiltration of intratumoral CD8+ T cells. We demonstrated that PLA2G2A+ meCAFs substantially attenuated the antitumor ability of tumor infiltrating CD8+ T cells and facilitated tumor immune escape in PDAC. Mechanistically, PLA2G2A regulated the function of CD8+ T cells as a pivotal soluble mediator via MAPK/Erk and NF-κB signaling pathways. In conclusion, our study identified the unrecognized role of PLA2G2A+ meCAFs in promoting tumor immune escape by impeding the antitumor immune function of CD8+ T cells, and strongly suggested PLA2G2A as a promising biomarker and therapeutic target for immunotherapy in PDAC.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.