Cuproptosis-triggering nanomedicine boosts antitumor immunotherapy

Cuproptosis, a copper-dependent programmed cell death triggered by mitochondrial copper accumulation and subsequent proteotoxic stress, has emerged as a promising strategy to enhance antitumor immunity. However, conventional cuproptosis inducers face critical limitations such as short blood circulation half-lives, dose-dependent systemic toxicity, and inadequate tumor targeting‌.‌ To address these challenges, advanced nanoplatforms have been developed to enable precise tumor-targeted cuproptosis induction and immune activation. This review summarizes the immune-activating mechanisms of cuproptosis, including its roles in promoting immune cell maturation and infiltration, remodeling the immunosuppressive tumor microenvironment, modulating immune checkpoint molecule expression, and activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. We highlight cutting-edge advancements in nanomaterial-based strategies for triggering cuproptosis, which enhance antitumor immunity whether used as a single treatment or in combination with other antitumor modalities. The current challenges in translating cuproptosis-based therapies into clinical applications are proposed to promote the development of cuproptosis-triggering nanomedicines as next-generation immunotherapy strategy.