Antitumor immunotherapeutic nanoagents enable molecular-photoswitching-based dynamic regulation of enzymatic activity of IDO1 for blocking immune evasion

We have fabricated a new type of MOFs-based nanoagent (SP@POMU-A) capable of suppressing tumor progression and metastasis by blocking immune evasion based on the molecular-photoswitching-enabled dynamic regulation of the enzymatic activity of IDO1. SP@POMU-A undergoes site-specific disintegration in lysosomes and releases the photosensitizer porphyrin, biometallic ion Mg²⁺, and molecular photoswitch spiropyran (SP), with them playing distinct roles in enabling immunotherapy via a highly synergistic manner. Porphyrin and Mg²⁺ synergistically prime the adaptive antitumor immune response based on the photosensitization ability of the former and adjuvant-like activity of the latter, respectively. SP upon phototriggering isomerizes to merocyanine with the latter capable of inactivating IDO1 and therefore blocking its role in tumor immune evasion. Thus, SP@POMU-A upon phototriggering can boost antitumor immunity and simultaneously block immune evasion, eventually potently inhibiting the tumor progression. The ability of SP@POMU-A to confer immunological memory for mounting a specific immune response upon re-exposure to the invasion of tumor cells has also been verified in an in vivo tumor model featured with typical pathological characteristics regarding immunosuppressive tumor microenvironment (TME). This proof-of-concept implementation opens a way to optically manipulate the enzymatic activity to relieve the immunosuppressive TME for synergistic antitumor with enhanced precision and efficacy.