An innovative approach to overcoming PD-1 resistance: Combined TIGIT blockade with nanophotothermal therapy

Abstract

Photothermal immunotherapy, especially combined with immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1), marks a breakthrough in cancer treatment. However, therapy often triggers compensatory upregulation of other immune checkpoints. This study introduces an advanced strategy to enhance the efficacy of photothermal immunotherapy by utilizing a novel nanocarrier that targets both PD-1 and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) immune checkpoints. The dual blockade could counteract the compensatory upregulation of immune checkpoints triggered by PD-1 targeted therapies alone. The nanocarrier of this work is composed of a ZrB2 photothermal core and a mesoporous silica layer, and finally coated with biocompatible polydopamine. This design could effectively deliver both TIGIT and PD-1 inhibitors directly to tumor sites, minimizing systemic side effects such as cytokine release syndrome. We demonstrate that this approach not only enhances cytotoxic responses of T and NK cells, but also promotes macrophage polarization towards a tumor-suppressing M1 phenotype dendritic cell maturation and immunogenic cell death. Our findings provide a promising avenue for cancer immunotherapy.