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

Currently, colorectal cancer ranks third in terms of global cancer incidence and second in terms of cancer-related mortality, posing a significant therapeutic challenge. However, the efficacy of immunotherapy is limited by the immunosuppressive tumor microenvironment, which is driven in part by T cell exhaustion. Herein, a copper-propranolol nanoplatform (Cu-PN NPs) rationally engineered by coordinating copper ions with propranolol and stabilizing the complex via mPEG-SH self-assembly was initially constructed. This design enables the codelivery of copper ions and propranolol, achieving dual functions: inducing copper-dependent cell death (cuproptosis) and apoptosis to trigger immunogenic cell death (ICD), and blocking ADRB1 on T cells to reverse exhaustion and restore effector function. In vitro studies in CT26 colorectal cancer (CRC) cells and patient-derived organoids (PDOs) confirmed enhanced cytotoxicity and ICD induction compared with those of monotherapy. In vivo, Cu-PN NPs significantly inhibited CRC tumour growth, reshaped the tumour microenvironment (TME) by attenuating T cell exhaustion, increasing cytokine secretion, and promoting dendritic cell maturation and CD8⁺ T cell activation. When combined with anti-PD-1 therapy, Cu-PN NPs markedly improved tumour control. This work introduces Cu-PN NPs as a dual-functional nanoplatform that integrates ICD induction with T cell reinvigoration via ADRB1 blockade, offering a promising strategy to enhance immune checkpoint blockade therapy against colorectal cancer.