Overcoming radiation-induced PD-L1 upregulation by novel gadolinium-palladium nanoplatforms for enhanced tumor radio-immunotherapy

Low-dose radiotherapy can lead to upregulation of PD-L1 expression in tumor cells, limiting the effectiveness of radio-immunotherapy. Currently, anti-PD-L1 drugs only disrupt the interaction of the PD-1/PD-L1 axis on the cell surface, without considering the immune regulatory ability of intracellular PD-L1. Additionally, antibody-bound PD-L1 can lead to internalization and recycling, allowing tumor cells to regain immune suppression. In this study, a novel PD-L1-affibody (Z PD-L1 )-grafted gadolinium-palladium nanoplatform incorporated with glucose oxidase (GOx) (GPGP) was fabricated to improve tumor-targeted magnetic resonance imaging (MRI) and synergistic radio-immunotherapy. GPGP with catalase- and peroxidase-like activity could catalyze the generation of oxygen to relieve tumor hypoxia and the generation of •OH to boost ferroptosis, respectively. GOx could enhance the nanoplatform’s dual nanozyme activity in a cascade, further sensitizing radiotherapy and intensifying subsequent immunogenic cell death. Crucially, GPGP induced AMPK phosphorylation and downregulated CMTM6, inhibiting intracellular PD-L1 production and blocking its transport to the cell membrane, thereby overcoming low-dose radiotherapy-induced PD-L1 upregulation. Systemic delivery of GPGP also demonstrated notable MRI contrast enhancement, providing precise imaging guidance for determining the optimal timing for radiotherapy. Therefore, GPGP has shown great potential in achieving effective MRI and collaborative tumor radio-immunotherapy.