Self-Assembled Nanoparticles with Kynureninase-Fc Fusion Protein and Pheophorbide A for Photodynamic Immunometabolic Cancer Therapy

Background/Objectives: Aberrant metabolism in tumors exacerbates the immunosuppressive tumor microenvironment. The immunosuppressive metabolite kynurenine inhibits the activation of effector T cells. Current antitumor drugs targeting kynurenine focus on small molecule inhibitors, which exhibit suboptimal efficacy in suppressing kynurenine generation owing to the diversity of kynurenine synthesis pathways. In contrast, kynureninase (KYNase) can directly metabolize kynurenine regardless of the production source. However, its delivery is hindered by short blood-circulation half-life and poor tumor accumulation. Additionally, photodynamic therapy (PDT) has been reported to synergize with immunotherapy, suggesting a potential combinatorial photodynamic immunometabolic cancer therapy with KYNase. Methods: A KYNase-Fc fusion protein was prepared to prolong blood circulation and enhance tumor accumulation of KYNase. Meanwhile, KYNase-Fc served as a nanocarrier for photosensitizer pheophorbide A (PhA) due to the high binding affinity between KYNase-Fc and PhA. Through self-assembly, KYNase-Fc/PhA nanoparticles (KYNase-Fc/PhA NPs) were prepared without extra carrier materials. Results: Compared with the PEGylated KYNase, KYNase-Fc exhibited significantly prolonged blood circulation, enhanced tumor accumulation and effective tumor suppression. Moreover, the prepared KYNase-Fc/PhA NPs facilitated rapid PhA tumor accumulation. The combined photodynamic immunometabolic therapy alleviated the immunosuppressive microenvironment and significantly inhibited the growth of subcutaneous 4T1 tumors in mice. Conclusions: KYNase-Fc offered a carrier-free nanomedicine for co-delivery of PhA for photodynamic immunometabolic antitumor therapy with enhanced efficacy, providing a promising platform for clinical translation.