Combined positron emission tomography-guided modified black phosphorus nanosheet-based photothermal therapy and anti programmed cell death protein ligand 1 therapy

Abstract

Background

Patients with cold tumors gain limited benefits from immune checkpoint blockade (ICB) therapy owing to low programmed cell death protein ligand 1 (PD-L1) expression and minimal immune cell infiltration. Mild photothermal therapy (PTT) using black phosphorus nanosheets (BPNSs) is a promising approach to enhance the efficacy of ICB therapy. However, to ensure that BPNS-based PTT-enhanced ICB therapy is clinically adaptable, a noninvasive, bedside-accessible imaging tool capable of monitoring the status of PD-L1 is imperative. We demonstrated that positron emission tomography (PET) using [⁶⁴Cu]HKP2202 precisely delineated PD-L1 expression in tumors receiving PTT.

Methods

BPNSs were modified with polyethylene glycol to prepare BPNS@PEG, which were then characterized. MC38 cells and tumor allografts were treated with BPNS@PEG followed by 808 nm near-infrared light exposure. PET using [⁶⁴Cu]HKP2202 was performed to monitor PD-L1 expression in vivo. We also evaluated whether the efficacy of ICB therapy improved after delivering BPNS@PEG-based PTT.

Results

BPNS@PEG had a well-defined lamellar structure with clear edges and an average size of 150 nm. PET and Western blotting assays indicated that PD-L1 expression was upregulated after BPNS@PEG and NIR-light treatment. Notably, the antitumor effect of anti PD-L1 therapy was enhanced in mice treated with BPNS@PEG-based PTT.

Conclusions

BPNS@PEG had the capacity to convert cold tumors into hot tumors to facilitate the efficacy of ICB therapy. Importantly, the complementary diagnostic PET radiotracer targeting PD-L1 allowed real-time monitoring of PD-L1 expression in the tumor microenvironment to guide ICB administration, holding great potential to achieve efficient and precise tumor immunotherapy.