Gao Ying, Zuo Lin, Zheng Yu, Sun Keyan, Gao Yunhui, Xu Xiaobo, Li Zengqiang, Zuo Daiying
Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
Breast Cancer Res. 2025 May 26;27(1):92. doi: 10.1186/s13058-025-02045-2.
Although immune checkpoint inhibitors (ICIs) have elicited desirable clinical outcomes, their effective application remains an obstacle due to immunologically "cold" tumors that manifest lymphocyte exhaustion or poor infiltration. Hence, exploring new therapeutic strategies to enhance antitumor immunity is important. NOTCH1 has emerged as an oncogene in multiple malignancies and is involved in regulating the tumor microenvironment (TME). Here, we demonstrated that NOTCH1 inhibition enhanced the expression of MHC class I (MHC-I) molecules and antigen presentation-related genes and increased the characteristics of immunogenic cell death (ICD), including calreticulin (CALR) translocation, ATP release, and endoplasmic reticulum (ER) stress signaling activation. These events enhance tumor antigen presentation and immunogenicity in triple-negative breast cancer (TNBC) cells. Furthermore, cellular senescence was observed after NOTCH1 inhibition. We also observed the senescence-associated secretory phenotype (SASP), including the generation of type I and type III interferons, which increased antigen presentation efficacy. Given that Ataxia-telangiectasia mutated kinase (ATM) is closely related to cellular senescence, we confirmed that the enhancement of immunogenicity mediated by NOTCH1 inhibition was dependent on the activation of ATM. More importantly, inhibition of NOTCH1 signaling sensitizes tumors to ICIs therapy in murine TNBC models and promotes antitumor immunity by upregulating lymphocyte infiltration. Collectively, our findings indicate that NOTCH1 inhibition enhances tumor immunogenicity and provides a rationale for developing new combination regimens comprising NOTCH1 inhibitors and ICIs for TNBC treatment.
尽管免疫检查点抑制剂（ICI）已取得了理想的临床效果，但由于表现出淋巴细胞耗竭或浸润不良的免疫“冷”肿瘤，其有效应用仍然是一个障碍。因此，探索增强抗肿瘤免疫力的新治疗策略很重要。NOTCH1已成为多种恶性肿瘤中的癌基因，并参与调节肿瘤微环境（TME）。在此，我们证明NOTCH1抑制增强了MHC I类（MHC-I）分子和抗原呈递相关基因的表达，并增加了免疫原性细胞死亡（ICD）的特征，包括钙网蛋白（CALR）易位、ATP释放和内质网（ER）应激信号激活。这些事件增强了三阴性乳腺癌（TNBC）细胞中的肿瘤抗原呈递和免疫原性。此外，NOTCH1抑制后观察到细胞衰老。我们还观察到衰老相关分泌表型（SASP），包括I型和III型干扰素的产生，这增加了抗原呈递效率。鉴于共济失调毛细血管扩张突变激酶（ATM）与细胞衰老密切相关，我们证实NOTCH1抑制介导的免疫原性增强依赖于ATM的激活。更重要的是，在小鼠TNBC模型中，NOTCH1信号的抑制使肿瘤对ICI治疗敏感，并通过上调淋巴细胞浸润来促进抗肿瘤免疫。总体而言，我们的研究结果表明NOTCH1抑制增强了肿瘤免疫原性，并为开发包含NOTCH1抑制剂和ICI的新联合方案用于TNBC治疗提供了理论依据。
