Engineering Modular Peptide Nanoparticles for Ferroptosis-Enhanced Tumor Immunotherapy.

Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors are promising for treating tumors but have limited efficacy due to the immunosuppressive tumor microenvironment. In this study, we develop an orchestrated nanoparticle system using modular peptide assemblies, where the co-assembled sequences are designed for the specific binding to the hydrophobic and hydrophilic domains, guiding the assembly process and enabling the customization of nanoparticle properties. We exploit the modularity of this platform to integrate a hydrophobic ferroptosis precursor, an IDO1 inhibitor, and a hydrophilic peptidic PD-L1 antagonist for optimizing therapeutic outcomes through ferroptosis-enhanced tumor immunotherapy. The resulting nanoparticles induce immunogenic ferroptosis, enhance the intratumoral function of T lymphocytes, suppress regulatory T cells, and effectively modulate the immunosuppressive tumor microenvironment, thereby facilitating regression of tumor growth. This work provides a modular peptide-based nanoparticle engineering strategy and holds significant potential for advancing cancer treatment.