The limited therapeutic effects of immunotherapy for most types of cancer stimulates the pursuit for efficient methods to improve its response rate. Herein we report the design and synthesis of a cascade-responsive molecular prodrug for tandem chemoimmunotherapy. This molecular prodrug first releases doxorubicin (DOX) in the mildly acidic tumor microenvironment (TME) to induce immunogenic cell death (ICD) of tumor cells. Caspase 3/7 released during tumor cell apoptosis liberates NLG919 from the prodrug, which inhibits the activity of indoleamine 2,3-dioxygenase (IDO) and results in relief of TME immunosuppression. Meanwhile, tumor-associated antigens and immune stimulatory cytokines released during ICD activate the immune response against the tumor, leading to synergistic chemoimmunotherapy. The efficacy of this prodrug is validated by in vitro and in vivo experiments, demonstrating the success of this strategy for cancer treatment.

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级联反应分子前药的串联化学免疫疗法

免疫疗法对大多数类型癌症的有限治疗效果刺激了人们寻求提高其反应率的有效方法。在此，我们报告了用于串联化学免疫疗法的级联反应分子前药的设计和合成。这种分子前药首先在弱酸性肿瘤微环境 (TME) 中释放阿霉素 (DOX) 以诱导肿瘤细胞的免疫原性细胞死亡 (ICD)。肿瘤细胞凋亡过程中释放的 Caspase 3/7 将 NLG919 从前药中释放出来，从而抑制吲哚胺 2,3-双加氧酶 (IDO) 的活性，从而缓解 TME 免疫抑制。同时，ICD期间释放的肿瘤相关抗原和免疫刺激性细胞因子激活对肿瘤的免疫反应，导致协同化学免疫治疗。该前药的功效通过以下方式验证体外和体内实验，证明了这种癌症治疗策略的成功。