Small cell lung cancers (SCLCs) have high mutational burden but are relatively unresponsive to immune checkpoint blockade (ICB). Using SCLC models, we demonstrate that inhibition of WEE1, a G2/M checkpoint regulator induced by DNA damage, activates the STING-TBK1-IRF3 pathway, which increases type I interferons (IFN-α and IFN-β) and pro-inflammatory chemokines (CXCL10 and CCL5), facilitating an immune response via CD8⁺ cytotoxic T cell infiltration. We further show that WEE1 inhibition concomitantly activates the STAT1 pathway, increasing IFN-γ and PD-L1 expression. Consistent with these findings, combined WEE1 inhibition (AZD1775) and PD-L1 blockade causes remarkable tumor regression, activation of type I and II interferon pathways, and infiltration of cytotoxic T cells in multiple immunocompetent SCLC genetically engineered mouse models, including an aggressive model with stabilized MYC. Our study demonstrates cell-autonomous and immune-stimulating activity of WEE1 inhibition in SCLC models. Combined inhibition of WEE1 plus PD-L1 blockade represents a promising immunotherapeutic approach in SCLC.

小细胞肺癌 (SCLC) 具有较高的突变负担，但对免疫检查点阻断 (ICB) 相对无反应。使用 SCLC 模型，我们证明了 WEE1（一种由 DNA 损伤诱导的 G2/M 检查点调节剂）的抑制会激活 STING-TBK1-IRF3 通路，从而增加 I 型干扰素（IFN-α 和 IFN-β）和促炎趋化因子（CXCL10 和 CCL5），通过 CD8 ⁺促进免疫反应细胞毒性 T 细胞浸润。我们进一步表明，WEE1 抑制同时激活了 STAT1 通路，增加了 IFN-γ 和 PD-L1 的表达。与这些发现一致，WEE1 抑制 (AZD1775) 和 PD-L1 阻断联合可导致多种免疫活性 SCLC 基因工程小鼠模型中显着的肿瘤消退、I 型和 II 型干扰素通路激活以及细胞毒性 T 细胞浸润，包括具有稳定MYC。我们的研究证明了 SCLC 模型中 WEE1 抑制的细胞自主和免疫刺激活性。WEE1 联合 PD-L1 阻断剂的联合抑制代表了一种有前途的 SCLC 免疫治疗方法。