Homotypic Targeted Photosensitive Nanointerferer for Tumor Cell Cycle Arrest to Boost Tumor Photoimmunotherapy

Recent advances in tumor immunotherapy mainly tend to remodel the immunosuppressive tumor microenvironment (TME) for immune enhancement. However, the complexity of TME makes it unlikely to achieve satisfactory therapeutic effects with any single intervention alone. Here, we focus on exposing intrinsic features of tumor cells to trigger direct pleiotropic antitumor immunity. We develop a photosensitive nanointerferer that is engineered with a nanoscale metal-organic framework decorated with tumor cell membranes for targeted delivery of a photosensitizer and small interfering RNA, which is used to knock down cyclin-dependent kinase 4 (Cdk4). Cdk4 blockade can arrest the cell cycle of tumor cells to facilitate antigen exposure and increase the expression level of programmed cell death protein ligand 1 (PD-L1). Under laser irradiation, photodynamic damage triggered by the nanointerferer induces the release of tumor antigens and recruitment of dendritic cells (DCs), thereby promoting the antitumor activity of CD8(+) T cells in combination with anti-PD-L1 antibodies. Ultimately, these events markedly retard tumor progression in a mouse model of ectopic colon tumor with negligible adverse effects. This study provides an alternative treatment for effective antitumor immunity by exciting the intrinsic potential of tumor cells to initiate immune responses while reducing immune-related toxicities.

Automated summary

Recent advances in tumor immunotherapy primarily focus on remodeling the immunosuppressive tumor microenvironment (TME) to enhance immune responses. However, the complexity of TME limits the effectiveness of single interventions. In this study, we developed a photosensitive nanointerferer that can trigger direct antitumor immune responses by exposing intrinsic features of tumor cells. The nanointerferer delivers a photosensitizer and small interfering RNA to inhibit cyclin-dependent kinase 4 (Cdk4) expression, leading to cell cycle arrest, antigen exposure, and increased expression of programmed cell death protein ligand 1 (PD-L1). Under laser irradiation, the nanointerferer induces photodynamic damage, releases tumor antigens, and recruits dendritic cells (DCs), promoting the activity of CD8(+) T cells in combination with anti-PD-L1 antibodies. This approach effectively inhibits tumor progression in a mouse model without significant adverse effects, providing an alternative treatment option for antitumor immunity.