Mounting evidence suggests that strategies combining DNA-damaging agents and stimulator of interferon genes (STING) agonists are promising cancer therapeutic regimens because they can amplify STING activation and remodel the immunosuppressive tumor microenvironment. However, a single molecular entity comprising both agents has not yet been developed. Herein, we designed two PtIV-MSA-2 conjugates (I and II) containing the DNA-damaging chemotherapeutic drug cisplatin and the innate immune-activating STING agonist MSA-2; these conjugates showed great potential as multispecific small-molecule drugs against pancreatic cancer. Mechanistic studies revealed that conjugate I upregulated the expression of transcripts associated with innate immunity and metabolism in cancer cells, significantly differing from cisplatin and MSA-2. An analysis of the tumor microenvironment demonstrated that conjugate I could enhance the infiltration of natural killer (NK) cells into tumors and promote the activation of T cells, NK cells and dendritic cells in tumor tissues. These findings indicated that conjugate I, which was created by incorporating a Pt chemotherapeutic drug and STING agonist into one molecule, is a promising and potent anticancer drug candidate, opening new avenues for small-molecule-based cancer metalloimmunotherapy.
越来越多的证据表明，结合DNA损伤剂和干扰素基因刺激因子（STING）激动剂的策略是前景广阔的癌症治疗方案，因为它们能够增强STING激活并重塑免疫抑制性肿瘤微环境。然而，目前尚未开发出同时包含这两种药物的单一分子实体。在此，我们设计了两种含有DNA损伤化疗药物顺铂和先天免疫激活STING激动剂MSA-2的PtIV-MSA-2偶联物（I和II），这些偶联物显示出作为抗胰腺癌多重特异性小分子药物的巨大潜力。机制研究表明，偶联物I能够上调癌细胞中与先天免疫和代谢相关转录物的表达，与顺铂和MSA-2存在显著差异。对肿瘤微环境的分析表明，偶联物I能够增强自然杀伤（NK）细胞向肿瘤的浸润，并促进肿瘤组织中T细胞、NK细胞和树突状细胞的活化。这些发现表明，通过将铂类化疗药物与STING激动剂整合到单一分子中制成的偶联物I，是一种前景广阔且强效的抗癌候选药物，为基于小分子的癌症金属免疫疗法开辟了新途径。
Combining cisplatin and a STING agonist into one molecule for metalloimmunotherapy of cancer
肿瘤(癌症)患者之家