Bräutigam Konstantin, Skok Kristijan, Szymonski Krzysztof, Rift Charlotte Vestrup, Karamitopoulou Eva
Institute of Cancer Research, Centre for Evolution and Cancer, London, SM2 5NG, United Kingdom; Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland.
Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria; Institute of Biomedical Sciences, Medical Faculty of Medicine, University of Maribor, Maribor, Slovenia.
Cancer Lett. 2025 Jul 10;622:217699. doi: 10.1016/j.canlet.2025.217699. Epub 2025 Apr 7.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly malignancies with a highly immunosuppressive tumor immune microenvironment (TIME) that hinders effective therapy. PDAC is characterized by significant heterogeneity in immune cell composition, spatial distribution and activation states, which impacts tumor progression and treatment response. Tumour-infiltrating lymphocytes (TILs), including CD4 T-helper cells, CD8 cytotoxic T-cells and FOXP3 regulatory T-cells, play a key role in immune regulation, yet PDAC is largely an immunologically "cold" tumour with limited effector T-cell infiltration. The surrounding cellular microenvironment, particularly Cancer Associated Fibroblasts (CAFs) and macrophages, contributes to immune evasion by promoting a fibrotic and desmoplastic barrier that limits TIL infiltration. The prognostic significance of TILs is increasingly recognized, with higher densities correlating with improved survival, whereas regulatory T-cell infiltration and immunosuppressive stromal interactions are associated with poor outcomes. Emerging therapeutic strategies targeting the TIME (e.g., CAFs), immune checkpoint inhibitors, and TIL-based therapies offer the potential to overcome resistance. Future research must focus on optimizing immunotherapy strategies and unravelling the complex stromal-immune interactions to improve clinical translation.
胰腺导管腺癌（PDAC）仍然是最致命的恶性肿瘤之一，其肿瘤免疫微环境（TIME）具有高度免疫抑制性，阻碍了有效治疗。PDAC的特征在于免疫细胞组成、空间分布和激活状态存在显著异质性，这会影响肿瘤进展和治疗反应。肿瘤浸润淋巴细胞（TILs），包括CD4辅助性T细胞、CD8细胞毒性T细胞和FOXP3调节性T细胞，在免疫调节中起关键作用，但PDAC在很大程度上是一种免疫“冷”肿瘤，效应T细胞浸润有限。周围的细胞微环境，特别是癌症相关成纤维细胞（CAFs）和巨噬细胞，通过促进纤维化和促结缔组织增生屏障来限制TIL浸润，从而导致免疫逃逸。TILs的预后意义越来越受到认可，较高的密度与生存率提高相关，而调节性T细胞浸润和免疫抑制性基质相互作用则与不良预后相关。针对TIME（如CAFs）的新兴治疗策略、免疫检查点抑制剂和基于TIL的疗法提供了克服耐药性的潜力。未来的研究必须专注于优化免疫治疗策略并阐明复杂的基质-免疫相互作用，以改善临床转化。
