A Sandwich-like metabolic regulator activated γδ T cells for dual immunotherapy.

Despite its clinical promise, immunotherapy remains constrained by its reliance on αβ T cells, which face intrinsic limitations such as major histocompatibility complex restriction and T cell exhaustion. To overcome these barriers, we developed a metabolism regulator, CPCM@HA, was developed to co-activate αβ and γδ T cells for potent dual immunotherapy. Following CPCM@HA endocytosis, the loaded Cu and metformin (Met) were selectively released in response to the acidic tumor microenvironment, inducing mitochondrial dysfunction and triggering apoptosis via excessive ROS and NO generation. This process enhanced antigen presentation and αβ T cell activation. Importantly, Met-mediated glycolysis suppression synergized with Cu-elicited cuproptosis to cripple the TCA cycle and oxidative phosphorylation, leading to energy metabolism stress and AMPK-driven γδ T cell activation. This dual-pronged immunoregulation facilitated dendritic cell maturation and BTN3A expression, reprogrammed the tumor-associated macrophages towards the tumoricidal M1 phenotype, and reversed the immunosuppressive tumor microenvironment. Consequently, tumor proliferation and metastasis were significantly suppressed, resulting in robust anti-tumor immunity. Collectively, this work not only proposed a promising strategy for potentiating immunotherapy through dual T cell activation and metabolic modulation, but also provided new insights to circumvent the limitations of immunotherapy in cancer treatment.