Cancer-associated fibroblasts (CAFs) perform diverse roles and can modulate therapy responses¹. The inflammatory environment within tumours also influences responses to many therapies, including the efficacy of oncolytic viruses²; however, the role of CAFs in this context remains unclear. Furthermore, little is known about the cell signalling triggered by heterotypic cancer cell–fibroblast contacts and about what activates fibroblasts to express inflammatory mediators^1,3. Here, we show that direct contact between cancer cells and CAFs triggers the expression of a wide range of inflammatory modulators by fibroblasts. This is initiated following transcytosis of cytoplasm from cancer cells into fibroblasts, leading to the activation of STING and IRF3-mediated expression of interferon-β1 and other cytokines. Interferon-β1 then drives interferon-stimulated transcriptional programs in both cancer cells and stromal fibroblasts and ultimately undermines the efficacy of oncolytic viruses, both in vitro and in vivo. Further, targeting IRF3 solely in stromal fibroblasts restores oncolytic herpes simplex virus function.

癌症相关成纤维细胞 (CAF) 发挥着不同的作用，并且可以调节治疗反应¹ 。肿瘤内的炎症环境也会影响对许多疗法的反应，包括溶瘤病毒的功效² ；然而，CAF 在这方面的作用仍不清楚。此外，人们对异型癌细胞-成纤维细胞接触触发的细胞信号传导以及激活成纤维细胞表达炎症介质的因素知之甚少^1,3 。在这里，我们发现癌细胞和 CAF 之间的直接接触会触发成纤维细胞表达多种炎症调节剂。这是在细胞质从癌细胞转胞吞进入成纤维细胞后启动的，导致 STING 激活和 IRF3 介导的干扰素 β1 和其他细胞因子的表达。然后，干扰素-β1 在癌细胞和基质成纤维细胞中驱动干扰素刺激的转录程序，并最终在体外和体内破坏溶瘤病毒的功效。此外，仅靶向基质成纤维细胞中的 IRF3 可恢复溶瘤单纯疱疹病毒功能。