干扰素 (IFN) 反应对于免疫检查点抑制 (ICI) 治疗的有效性至关重要。我们之前的研究表明，KRAS（克尔斯滕大鼠肉瘤病毒）突变会损害结直肠癌（CRC）中的 IFN 反应，但机制尚不清楚。在这里，我们证明 KRAS 通过下调 DExD/H-box 解旋酶 6 (DDX60) 来加速双链 RNA (dsRNA) 降解，损害 dsRNA 传感和 IFN 响应。 DDX60 在这里被确定为 KRAS 靶标，可以与 dsRNA 结合，以防止 RNA 诱导的沉默复合物 (RISC) 介导的降解。过表达 DDX60 会诱导 dsRNA 积累，重新激活 IFN 信号传导，并增加 CRC 对 ICI 治疗的敏感性。从机制上讲，KRAS 通过 AKT（也称为蛋白激酶 B）-GSK3β（糖原合酶激酶 3 β）途径抑制 STAT3 磷酸化，从而抑制 STAT3 驱动的 DDX60 转录。我们的研究结果揭示了 KRAS 在 dsRNA 稳态中的作用，提出了将“冷”肿瘤转化为“热”肿瘤并克服 KRAS 突变的 CRC 中 ICI 耐药的潜在策略。

The interferon (IFN) response is vital for the effectiveness of immune checkpoint inhibition (ICI) therapy. Our previous research showed that KRAS (Kirsten rat sarcoma viral) mutation impairs the IFN response in colorectal cancer (CRC), with an unclear mechanism. Here, we demonstrate that KRAS accelerates double-stranded RNA (dsRNA) degradation, impairing dsRNA sensing and IFN response by down-regulating DExD/H-box helicase 6 (DDX60). DDX60 was identified as a KRAS target here and could bind to dsRNAs to protect against RNA-induced silencing complex (RISC)-mediated degradation. Overexpressing DDX60 induced dsRNA accumulation, reactivated IFN signaling, and increased CRC sensitivity to ICI therapy. Mechanistically, KRAS engaged the AKT (also known as protein kinase B)-GSK3β (glycogen synthase kinase-3 beta) pathway to suppress STAT3 phosphorylation, thereby inhibiting STAT3-driven DDX60 transcription. Our findings reveal a role for KRAS in dsRNA homeostasis, suggesting potential strategies to convert "cold" tumors to "hot" and to overcome ICI resistance in CRC with KRAS mutations.