Tumor Microenvironment Reprogramming via Copper-Enriched Black Phosphorus Nanoplatform for Cuproptosis-Sensitized...

Area of Science:

• Nanomedicine
• Cancer Immunotherapy
• Radiotherapy

Background:

• Radioimmunotherapy (RIT) efficacy is hindered by immunosuppressive tumor microenvironments (TME) and limited therapeutic windows.
• Overcoming radioresistance and immunosuppression is crucial for effective deep-seated and metastatic tumor treatment.

Purpose of the Study:

• To develop a novel nanoplatform for enhanced RIT by sensitizing tumors to radiation, inducing cuproptosis, and reprogramming the TME.
• To engineer a PEGylated copper-loaded black phosphorus nanoplatform (BPNS@Cu-PEG) for combined therapeutic effects.

Main Methods:

• Synthesized BPNS@Cu-PEG with high copper loading (93%).
• Evaluated radiosensitizing and cuproptosis-inducing capabilities.
• Investigated TME reprogramming mechanisms: GSH depletion, ROS amplification, hypoxia alleviation, and M2-to-M1 macrophage repolarization.
• Assessed in vitro and in vivo antitumor immune effects.

Main Results:

• BPNS@Cu-PEG effectively induced cuproptosis and immunogenic cell death (ICD) in vitro.
• The nanoplatform reprogrammed the TME by depleting GSH, amplifying ROS, alleviating hypoxia, and repolarizing macrophages.
• In vivo, BPNS@Cu-PEG inhibited tumor growth, stimulated antitumor immunity under low-dose radiotherapy, and demonstrated a favorable safety profile.

Conclusions:

• Established a copper-based, low-dose RIT strategy using BPNS@Cu-PEG.
• The nanoplatform effectively counteracts radioresistance and promotes systemic antitumor immunity.
• BPNS@Cu-PEG offers a potent approach to broaden RIT's therapeutic applications and safety.