Synergistic photothermal cancer immunotherapy by Cas9 ribonucleoprotein-based copper sulfide nanotherapeutic platform targeting PTPN2

Photothermal therapy (PTT) is a promising strategy for the treatment of advanced malignant neoplasm. However, the anti-tumor efficacy by PTT alone is insufficient to control tumor growth and metastasis. Here, we report a multifunctional nanotherapeutic system exerting a combined PTT and immunotherapy to synergistically enhance the therapeutic effect on melanoma. In particular, we selected the semiconductor nanomaterial copper sulfide (CuS), which served not only as a near-infrared (NIR) light-triggered photothermal converter for tumor hyperthermia but as a basic carrier to modify Cas9 ribonucleoprotein targeting PTPN2 on its surface. Efficient PTPN2 depletion was observed after the treatment of CuS-RNP@PEI nanoparticles, which caused the accumulation of intratumoral infiltrating CD8 T lymphocytes in tumor-bearing mice and upregulated the expression levels of IFN-gamma and TNF-alpha in tumor tissue, thus sensitizing tumors to immunotherapy. In addition, the effect worked synergistically with tumor ablation and immunogenic cell death (ICD) induced by PTT to amplify antitumor efficacy. Taken together, this exogenously controlled method provides a simple and effective treatment option for advanced malignant neoplasm.

Automated summary

This study introduces a multifunctional nanotherapeutic system utilizing copper sulfide (CuS) nanomaterial for combined photothermal therapy (PTT) and immunotherapy on melanoma. The system effectively depletes PTPN2, boosts intratumoral CD8 T lymphocytes, and enhances the response to immunotherapy. These synergistic effects, along with tumor ablation and immunogenic cell death induced by PTT, provide a promising treatment option for advanced malignant neoplasm.