肿瘤微环境中的癌相关成纤维细胞（CAFs）对天然杀伤（NK）细胞的功能造成影响，而NK细胞已被证明是一种有前途的治疗方式。CAFs和NK细胞之间的相互作用有重要的免疫反应抑制作用，表明针对CAFs的治疗是有效的NK介导肿瘤杀伤的潜在靶点。为了克服CAFs引起的NK功能障碍，我们选择了一种抗纤维化药物nintedanib进行协同治疗。为了评估协同治疗的疗效，我们建立了体外的3D Capan2 /患者来源的CAFs球模型或体内的混合Capan2 / CAF 肿瘤异种移植模型。通过体外实验揭示了NK介导的nintedanib 协同治疗的分子机制。随后评估了体内的治疗协同效果。此外，通过免疫组织化学方法测量了患者来源的肿瘤切片中靶蛋白的表达得分。Nintedanib阻断了血小板衍生生长因子受体β（PDGFRβ）信号通路，减少了CAFs的激活和生长，显著降低了CAFs分泌的IL-6。此外，nintedanib的联合使用提高了介质素（MSLN）靶向嵌合抗原受体-NK介导的对CAFs /肿瘤球体或异种移植模型的肿瘤杀伤能力。协同组合导致了强烈的NK细胞浸润。Nintedanib单独使用没有效果，而IL-6跨越信号阻断改善了NK细胞的功能。MSLN和PDGFRβ + -CAFs人群区域的表达组合是一种潜在的预后/治疗标志物，并与较差的临床结局相关。我们针对PDGFRβ + -CAF含量的胰腺癌的策略可以提高胰腺导管腺癌的治疗效果。

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) contribute to an impaired functionality of natural killer (NK) cells that have emerged as a promising therapeutic modality. The interaction between CAFs and NK cells within the TME exerts major inhibitory effects on immune responses, indicating CAF-targeted therapies as potential targets for effective NK-mediated cancer killing.To overcome CAF-induced NK dysfunction, we selected an antifibrotic drug, nintedanib, for synergistic therapeutic combination. To evaluate synergistic therapeutic efficacy, we established an in vitro 3D Capan2/patient-derived CAF spheroid model or in vivo mixed Capan2/CAF tumor xenograft model. The molecular mechanism of NK-mediated synergistic therapeutic combination with nintedanib was revealed through in vitro experiments. In vivo therapeutic combination efficacy was subsequently evaluated. Additionally, the expression score of target proteins was measured in patient-derived tumor sections by the immunohistochemical method.Nintedanib blocked the platelet-derived growth factor receptor β (PDGFRβ) signaling pathway and diminished the activation and growth of CAFs, markedly reducing CAF-secreted IL-6. Moreover, coadministration of nintedanib improved the mesothelin (MSLN) targeting chimeric antigen receptor-NK-mediated tumor killing abilities in CAF/tumor spheroids or a xenograft model. The synergistic combination resulted in intense NK infiltration in vivo. Nintedanib alone exerted no effects, whereas blockade of IL-6 trans-signaling ameliorated the function of NK cells. The combination of the expression of MSLN and the PDGFRβ+-CAF population area, a potential prognostic/therapeutic marker, was associated with inferior clinical outcomes.Our strategy against PDGFRβ+-CAF-containing pancreatic cancer allows improvements in the therapy of pancreatic ductal adenocarcinoma.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.