Reinvigorating CD8⁺ T cells through ADRB1 blockade using copper-propranolol nanoparticles for enhanced immune...

Area of Science:

• Oncology
• Nanomedicine
• Immunotherapy

Background:

• Colorectal cancer (CRC) presents a major global health challenge, with limited treatment options due to immunosuppressive tumor microenvironments and T cell exhaustion.
• Current immunotherapies face challenges in overcoming the immunosuppressive tumor microenvironment (TME) that hinders their efficacy.

Purpose of the Study:

• To develop a dual-functional nanoplatform, copper-propranolol nanoparticles (Cu-PN NPs), for enhanced colorectal cancer treatment.
• To investigate the potential of Cu-PN NPs to induce immunogenic cell death (ICD) and reverse T cell exhaustion.

Main Methods:

• Engineered copper-propranolol nanoplatform (Cu-PN NPs) by coordinating copper ions with propranolol and stabilizing with mPEG-SH.
• Evaluated Cu-PN NPs in vitro using CT26 colorectal cancer cells and patient-derived organoids (PDOs).
• Assessed Cu-PN NPs efficacy in vivo in a colorectal cancer mouse model, including combination therapy with anti-PD-1.

Main Results:

• Cu-PN NPs demonstrated enhanced cytotoxicity and ICD induction in vitro compared to monotherapy.
• In vivo studies showed significant inhibition of CRC tumor growth and a reshaped TME.
• Cu-PN NPs attenuated T cell exhaustion, increased cytokine secretion, promoted dendritic cell maturation, and enhanced CD8+ T cell activation.
• Combination therapy with anti-PD-1 markedly improved tumor control.

Conclusions:

• Cu-PN NPs effectively induce immunogenic cell death (ICD) and reverse T cell exhaustion in colorectal cancer.
• This dual-action nanoplatform offers a promising strategy to enhance immune checkpoint blockade therapy for colorectal cancer.
• Cu-PN NPs represent a novel therapeutic approach by integrating ICD induction with T cell reinvigoration via ADRB1 blockade.