免疫抑制性肿瘤微环境（TME）仍然是肿瘤控制的主要障碍，并导致免疫检查点阻断（ICB）治疗的反应不佳。因此，开发触发 TME 炎症反应的可行治疗策略可以提高 ICB 疗效。线粒体在炎症调节和肿瘤免疫原性诱导中发挥重要作用。在此，我们报告了一类小分子的发现和表征，这些小分子可以重现水性自组装行为，特别针对细胞器（例如线粒体），并增强肿瘤细胞的免疫原性。从机制上讲，该纳米组装平台动态地重新连接线粒体，诱导内质网应激，并导致细胞凋亡/凋亡相关的免疫原性细胞死亡。治疗后，应激和垂死的肿瘤细胞可以充当预防性或治疗性癌症疫苗。在对 PD-1 阻断具有内在或获得性耐药性的癌症临床前小鼠模型中，局部施用纳米组件会刺激免疫沉默的 TME，并与 ICB 疗法协同作用，产生有效的抗肿瘤免疫。这种化学编程的小分子免疫增强剂的作用与常规细胞毒性疗法截然不同，并为同步和动态调整先天免疫提供了一种有前景的策略，以实现无痕癌症治疗并克服癌症中的免疫抑制。© 2024。作者。

The immunosuppressive tumor microenvironment (TME) remains a major obstacle to tumor control and causes suboptimal responses to immune checkpoint blockade (ICB) therapy. Thus, developing feasible therapeutic strategies that trigger inflammatory responses in the TME could improve the ICB efficacy. Mitochondria play an essential role in inflammation regulation and tumor immunogenicity induction. Herein, we report the discovery and characterization of a class of small molecules that can recapitulate aqueous self-assembly behavior, specifically target cellular organelles (e.g., mitochondria), and invigorate tumor cell immunogenicity. Mechanistically, this nanoassembly platform dynamically rewires mitochondria, induces endoplasmic reticulum stress, and causes apoptosis/paraptosis-associated immunogenic cell death. After treatment, stressed and dying tumor cells can act as prophylactic or therapeutic cancer vaccines. In preclinical mouse models of cancers with intrinsic or acquired resistance to PD-1 blockade, the local administration of nanoassemblies inflames the immunologically silent TME and synergizes with ICB therapy, generating potent antitumor immunity. This chemically programmed small-molecule immune enhancer acts distinctly from regular cytotoxic therapeutics and offers a promising strategy for synchronous and dynamic tailoring of innate immunity to achieve traceless cancer therapy and overcome immunosuppression in cancers.© 2024. The Author(s).