免疫疗法彻底改变了癌症治疗，但其疗效取决于肿瘤中强大的免疫反应。肿瘤抑制因子 p53 的沉默在肿瘤中很常见，会影响不同免疫细胞的招募和激活，导致免疫逃避和治疗反应不佳。我们发现 p53 激活钉合肽 MDM2/MDMX 抑制剂 Sulanemadlin (ALRN-6924) 可在体外和体内抑制 p53 野生型癌细胞的生长。在携带 p53 野生型 CT26.WT 肿瘤的小鼠中，PD-1 抑制剂 DX400 或 Sulanemadlin 单一疗法分别使肿瘤倍增时间延迟了 50% 和 37%，而联合疗法使肿瘤倍增时间缩短了 93%，导致中位数增加生存时间。 Sulanemadlin 治疗导致免疫原性增加，而与 PD-1 抑制的联合治疗导致淋巴细胞的肿瘤浸润增加。这种联合治疗策略有可能将部分应答者转变为免疫疗法的应答者，从而扩大 PD-1 靶向免疫疗法的患者目标群体。© 2024 作者。

Immunotherapy has revolutionized cancer treatment but its efficacy depends on a robust immune response in the tumor. Silencing of the tumor suppressor p53 is common in tumors and can affect the recruitment and activation of different immune cells, leading to immune evasion and poor therapy response. We found that the p53 activating stapled peptide MDM2/MDMX inhibitor Sulanemadlin (ALRN-6924) inhibited p53 wild-type cancer cell growth in vitro and in vivo. In mice carrying p53 wild-type CT26.WT tumors, monotherapy with the PD-1 inhibitor DX400 or Sulanemadlin delayed tumor doubling time by 50% and 37%, respectively, while combination therapy decreased tumor doubling time by 93% leading to an increased median survival time. Sulanemadlin treatment led to increased immunogenicity and combination treatment with PD-1 inhibition resulted in an increased tumor infiltration of lymphocytes. This combination treatment strategy could potentially turn partial responders into responders of immunotherapy, expanding the patient target group for PD-1-targeting immunotherapy.© 2024 The Author(s).