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-MnO@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 MnO-produced oxygen and induces ICD to reverse the immunosuppressive TME. In the light-off phase, Mn (from IDP and MnO-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 Mn to Mn, 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.