胰腺癌的特点是广泛的纤维炎症微环境。在癌发生过程中，正常基质细胞转化为细胞因子高的癌症相关成纤维细胞（CAF）。这种转化的机制，包括成纤维细胞衍生的细胞因子的调节和功能，人们知之甚少。因此，迄今为止，针对 CAF 进行治疗的努力都失败了。在这里，我们发现来自表达致癌 KRAS（胰腺癌标志性突变）的上皮细胞发出的信号激活成纤维细胞自分泌信号，从而驱动细胞因子白细胞介素 33 (IL-33) 的表达。在整个癌变过程中，间质 IL-33 表达保持高水平并依赖于上皮 KRAS；反过来，环境压力会诱导 IL-33 分泌。使用区室特异性 IL-33 敲除小鼠，我们观察到基质 IL-33 的缺乏会导致胰腺肿瘤微环境的多个成分（包括 CAF、骨髓细胞和淋巴细胞）发生深刻的重编程。值得注意的是，基质 IL-33 的缺失会导致 CD8 T 细胞浸润和激活增加，并最终减少肿瘤生长。

Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer associated fibroblasts (CAFs). The mechanisms underlying this conversion, including regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to target CAFs therapeutically have so far failed. Here, we show that signals from epithelial cells expressing oncogenic KRAS -a hallmark pancreatic cancer mutation- activate fibroblast autocrine signaling, which drives expression of the cytokine interleukin-33 (IL-33). Stromal IL-33 expression remains high and dependent on epithelial KRAS throughout carcinogenesis; in turn, environmental stress induces IL-33 secretion. Using compartment-specific IL-33 knockout mice, we observed that lack of stromal IL-33 leads to profound reprogramming of multiple components of the pancreatic tumor microenvironment, including CAFs, myeloid cells and lymphocytes. Notably, loss of stromal IL-33 leads to an increase in CD8+ T cell infiltration and activation, and, ultimately, reduced tumor growth.