Activatable Photosensitizer Prodrug for Self‐Amplified Immune Therapy via Pyroptosis

Immunotherapy is a promising cancer treatment, but its application is hindered by tumors' low immunogenicity and the difficulty of immune cell infiltration. Here, to address above issues and achieve targeted tumor treatment, we designed the first activated small molecule photosensitizer immune-prodrug HDIM based on pyroptosis, and proposed a self-amplified immune therapy strategy (SITS) for enhanced tumor therapy. HDIMcan be specifically activated by the tumor hypoxiaand then simultaneously initiate immuno-therapy and photodynamic therapy (PDT)-induced pyroptosis with NIR laser irradiation. Mechanism study demonstrated that the immunogenicity in tumor can be significantly enhanced by HDIM-induced pyroptosis and immune cells are recruited, thus effectively amplifying the therapeutic effect of the released immune drugs. As proof of application, we have utilized HDIM for primary tumor and distant tumor therapy. And the experiment results showed that compared to current monotherapy as well as simple combination therapy, the photosensitizer prodrug HDIM exhibited much superior tumor treatment effect owing to its synchronous activation of pyroptosis and immuno-therapy in tumor.