Dual-Regulated Biomimetic Nanocomposites For Promoted Tumor Photodynamic Immunotherapy

Area of Science:

• Biomedical Engineering
• Cancer Nanomedicine
• Immunotherapy

Background:

• The tumor microenvironment (TME) in triple-negative breast cancer is highly immunosuppressive, hindering effective immunotherapy.
• Phototherapy can induce immunogenic cell death (ICD) but also upregulates indoleamine 2,3-dioxygenase (IDO), creating an
• immune-metabolism
• loop that compromises treatment efficacy.

Purpose of the Study:

• To develop a novel nanomedicine, IMMGP, that synergistically combines phototherapy-induced ICD and metabolic reprogramming.
• To overcome the immunosuppressive TME and enhance antitumor immunity by breaking the
• immune-metabolism
• loop.

Main Methods:

• Development of IMMGP, comprising biomimetic IND-Mn@PM (IDP) and ICG-MnO2@PM (IMP).
• Utilizing IMP for photodynamic therapy (PDT) to induce ICD and ROS generation during light-on phase.
• Employing IDP and MnO2 redox reactions for sustained ROS generation and glutathione exhaustion during light-off phase, alongside indoximod (IND) release to downregulate IDO.

Main Results:

• IMMGP effectively kills cancer cells via photodynamic ROS generation and induces ICD, reversing the immunosuppressive TME.
• Sustained ROS generation and intratumoral GSH exhaustion promote dendritic cell maturation.
• Indoximod release downregulates IDO, inhibiting kynurenine metabolism and reinvigorating T cell-mediated immunity.
• IMMGP achieved nearly complete tumor inhibition (94.25%) by amplifying the immune response and sustaining an
• immunologically hot
• state.

Conclusions:

• IMMGP effectively breaks the
• immune-metabolism
• loop, amplifying antitumor immune responses.
• Dual-phase photodynamic immunotherapy mediated by IMMGP offers a promising novel approach in cancer nanomedicine.
• IMMGP demonstrates significant potential for treating triple-negative breast cancer by enhancing immunotherapy efficacy.