Dual-Regulated Biomimetic Nanocomposites For Promoted Tumor Photodynamic Immunotherapy

Effective tumor immunotherapy is hindered by an immunosuppressive tumor microenvironment (TME), especially in triple-negative breast cancer. Though phototherapy could induce immunogenic cell death (ICD) to increase antitumor immunity, the simultaneous upregulation of indoleamine 2,3-dioxygenase (IDO) induces the negative immunomodulatory effect termed as the "immune-metabolism" loop to compromise immunotherapeutic efficacy. Herein, we developed IMMGP consisting of biomimetic IND-Mn@PM (IDP) and ICG-MnO2@PM (IMP), which combines the phototherapy-induced ICD and metabolic reprogramming to solve the dilemma. During the light-on phase, IMP effectively kills cancer cells with potent photodynamic ROS generation with the assistance of MnO2-produced oxygen and induces ICD to reverse the immunosuppressive TME. In the light-off phase, Mn2+ (from IDP and MnO2-based redox reaction) elicits a Fenton-like reaction to relay ROS generation, which is further orchestrated with continuous exhaustion of intratumoral GSH by the conversion of Mn3+ to Mn2+, and promotes dendritic cell maturation. Moreover, the released indoximod (IND) downregulated IDO to inhibit kynurenine metabolism, which reinvigorates T cell-mediated antitumor immunity. Collectively, IMMGP amplifies the immune response by breaking the "immune-metabolism" loop and sustaining the "immunologically hot" state after phototherapy, thus leading to nearly complete tumor inhibition (94.25%). Thus, IMMGP-mediated dual-phase photodynamic immunotherapy offers a novel approach in cancer nanomedicine.