Photoactivatable Immunostimulatory Nanomedicine for Immunometabolic Cancer Therapy

A rationally designed immunostimulant (CC@SiO₂-PLG) with a photoactivatable immunotherapeutic function for synergetic tumor therapy is reported. This CC@SiO₂-PLG nanoplatform comprises catalase and a photosensitizer (Ce6) co-encapsulated in a silica capsule, to which an immunostimulant is conjugated through a reactive oxygen species-cleavable linker. After accumulating in tumor tissue, CC@SiO₂-PLG generates O₂ to relieve tumor hypoxia and promotes the production of singlet oxygen (¹O₂) upon laser irradiation, resulting in not only tumor destruction but also the release of tumor-associated antigens (TAAs). Simultaneously, the linker breakage by the photoproduced ¹O₂ leads to the remote-controlled release of conjugated indoleamine 2,3-dioxygenase (IDO) inhibitor from CC@SiO₂-PLG and consequent immunosuppressive tumor microenvironment reversion. The released TAAs in conjunction with the inhibition of the IDO-mediated tryptophan/kynurenine metabolic pathway induced a boosted antitumor immune response to the CC@SiO₂-PLG-mediated phototherapy. Therefore, the growth of primary/distant tumors and lung metastases in a mouse xenograft model was greatly inhibited, which was not achievable by phototherapy alone.