Metal-phenolic nanocapsules enable a self-amplifying cuproptosis-STING cascade for synergistic cancer immunotherapy.

Abstract

Immunosuppressive tumor microenvironment remains a major obstacle to effective cancer immunotherapy, largely due to insufficient initiation and amplification of antitumor immune responses. Herein, we report a mechanism-driven nanotherapeutic strategy that establishes a self-amplifying cuproptosis-STING cascade to overcome tumor immune resistance. The multifunctional copper/manganese-phenolic nanocapsules (HLCM@Cap) undergo pH-responsive release in the acidic tumor microenvironment, enabling efficient intratumoral copper accumulation and triggering cuproptosis characterized by mitochondrial dysfunction and proteotoxic stress. The resulting release of mitochondrial DNA activates the cGAS-STING pathway, while concurrently released Mn²⁺ further amplifies STING signaling. Meanwhile, Mn²⁺ also enables T₁-weighted magnetic resonance imaging for real-time monitoring of intratumoral nanocapsule accumulation and release, allowing optimization of the administration window. To counteract tumor adaptive resistance, a Wnt/β-catenin inhibitor is incorporated to suppress glycolytic reprogramming and copper efflux, thereby enhancing intracellular copper toxicity and metabolic stress. This coordinated regulation forms a positive feedback loop that reinforces STING activation through persistent damage-associated signaling. Consequently, the cascade promotes dendritic cell maturation, enhances CD8⁺ T cell infiltration, remodels the immunosuppressive tumor microenvironment, and induces durable immune memory. In a 4T1 tumor model, HLCM@Cap achieves significant antitumor and antimetastatic effects, which are further enhanced in combination with αPD-L1 therapy. Overall, this work presents a self-amplifying cuproptosis-STING cascade to convert immunologically "cold" tumors into "hot" tumors, offering a promising and translatable strategy for synergistic cancer immunotherapy.