Enhanced Upconversion Luminescent Nanocarrier for Effective Tumor-Targeted Photodynamic Therapy Combined with Immunotherapy.

Combination cancer therapy, a treatment modality combining two or more therapeutic strategies, has attracted attention for treating various types of cancer. In this study, we produced near-infrared (NIR)-induced multi-shell upconversion nanoparticle (MUN)-based therapeutic nanocarriers co-loaded with chlorin e6 (Ce6) and indoximod (IND) (FMUN3-Ce6/IND) to combine tumor-targeted photodynamic therapy (PDT) with immunotherapy. Upconversion nanoparticles doped with rare-earth elements are synthesized into multi-shell structures to improve their upconversion luminescence efficiency. In particular, their emission intensity in the red region, which is the excitation wavelength of Ce6, increased by ∼519 times compared with the core nanoparticles, which enhanced the PDT effect. The MUN-based nanocarriers showed more than 18-fold better ROS generation than free Ce6 under 808 nm NIR laser irradiation. FMUN3-Ce6/IND nanocarriers conjugated with a folic acid ligand showed particularly high phototoxicity to HeLa cells overexpressing folate receptors due to their active targeting effect. FMUN3-Ce6/IND nanocarriers increased the ratio of CD3+CD8+ to CD3+CD4+FoxP3+ T cells by approximately 5.4-fold compared to FMUN3-Ce6 without IND, indicating that inhibition of Trp metabolism by IND effectively promotes CD8+ T cell proliferation and suppresses Treg cells, thereby enhancing the antitumor immune response. Furthermore, the synergistic antitumor efficacy of FMUN3-Ce6/IND combining PDT and immunotherapy under in vivo conditions is demonstrated. These results suggest that multi-shell FMUN-based nanocarriers offer a promising platform for synergistic combination therapy, addressing the limitations of monotherapy with IDO inhibitors and overcoming the restricted tissue penetration and low ROS generation associated with conventional PDT.