Although chemotherapy can stimulate antitumor immunity by inducing interferon (IFN) response, the functional role of tumor-associated macrophages in this scenario remains unclear. Here, we found that IFN-activated proinflammatory macrophages after neoadjuvant chemotherapy enhanced antitumor immunity but promoted cancer chemoresistance. Mechanistically, IFN induced expression of cytoplasmic long noncoding RNA IFN-responsive nuclear factor-κB activator (IRENA) in macrophages, which triggered nuclear factor-κB signaling via dimerizing protein kinase R and subsequently increased production of protumor inflammatory cytokines. By constructing macrophage-conditional IRENA-knockout mice, we found that targeting IRENA in IFN-activated macrophages abrogated their protumor effects, while retaining their capacity to enhance antitumor immunity. Clinically, IRENA expression in post-chemotherapy macrophages was associated with poor patient survival. These findings indicate that lncRNA can determine the dichotomy of inflammatory cells on cancer progression and antitumor immunity and suggest that targeting IRENA is an effective therapeutic strategy to reversing tumor-promoting inflammation.

尽管化疗可以通过诱导干扰素 (IFN) 反应来刺激抗肿瘤免疫，但肿瘤相关巨噬细胞在这种情况下的功能作用仍不清楚。在这里，我们发现新辅助化疗后 IFN 激活的促炎巨噬细胞增强了抗肿瘤免疫，但促进了癌症的化学抗性。从机制上讲，IFN 诱导巨噬细胞中细胞质长链非编码 RNA IFN 反应性核因子-κB 激活剂 (IRENA) 的表达，这通过二聚化蛋白激酶 R 触发核因子-κB 信号传导，随后增加了促肿瘤炎性细胞因子的产生。通过构建巨噬细胞条件性 IRENA 敲除小鼠，我们发现在 IFN 激活的巨噬细胞中靶向 IRENA 消除了它们的促癌作用，同时保留了它们增强抗肿瘤免疫的能力。临床上，化疗后巨噬细胞中 IRENA 的表达与患者生存率低有关。这些发现表明lncRNA可以确定炎症细胞对癌症进展和抗肿瘤免疫的二分法，并表明靶向IRENA是逆转促肿瘤炎症的有效治疗策略。