Plant-Derived Thylakoids Potentiate Copper-Mediated Multimodal Cell Death via Hypoxia Alleviation for Synergistic Antitumor Therapy.

Cuproptosis is a copper-dependent programmed cell death mechanism characterized by mitochondrial copper accumulation, which leads to protein aggregation and proteotoxic stress, offering considerable anti-cancer potential. However, the hypoxic tumor microenvironment (TME) activates HIF-1α signaling, promoting glycolytic metabolism and reducing sensitivity to cuproptosis. To overcome this limitation, we designed TC@UN/G, a system comprising a metal-organic framework (UN) for copper delivery, oxygen-generating thylakoids (T) to alleviate hypoxia via photosynthesis, and a thermosensitive F127 hydrogel (G) for localized sustained release through peritumoral injection. Upon peritumoral injection and light illumination, thylakoids produced oxygen, relieving hypoxia and restoring mitochondrial function. This sensitized tumor cells to cuproptosis and concurrently triggered ferroptosis and immunogenic cell death, thereby activating antitumor immunity. In the cancer model, TC@UN/G+IL suppressed tumor growth and remodeled the TME. This approach offers a holistic strategy for solid tumor therapy by modulating the TME, potentiating cuproptosis, and activating the immune response.