Multifunctional copper-based nanoparticles potentiate colorectal cancer immunotherapy via synergistic metabolic remodeling and cGAS-STING pathway activation.

Microsatellite-stable (MSS) colorectal cancer (CRC) resists immunotherapy due to its immunosuppressive tumor microenvironment (TME). The cGAS-STING pathway, a key regulator of innate immunity, offers a promising strategy to overcome the immunotherapy resistance in CRC. However, its limited endogenous activation, coupled with the immunosuppression driven by lactate accumulation, significantly compromises the efficacy of standalone STING activation. In response, we developed a multifunctional copper-based metal-organic framework (Cu-MOF) nanoparticle co-loaded with the STING agonist SR-717 and the glycolysis inhibitor 3-bromopyruvate (3-BP), coated with tumor cell membranes (termed BR@CuM@CM), to achieve integrated metabolic modulation and immune activation. BR@CuM@CM nanoparticle achieves tumor-specific accumulation via homotypic targeting and undergo glutathione-responsive degradation to trigger drug release. The released SR-717 activates the STING pathway, promoting dendritic cell (DC) maturation and thereby enhancing cytotoxic T-cell recruitment. Concurrently, Cu²⁺ triggers Fenton-like reactions to generate reactive oxygen species (ROS), inducing mitochondrial DNA release and further amplifying STING signaling. Meanwhile, 3-BP suppresses lactate production by inhibiting glycolysis, which not only repolarizes M2-type tumor-associated macrophages toward the M1 phenotypes and suppresses regulatory T cell (Treg) infiltration, but also alleviates cGAS lactylation to enhance cGAS activity and amplifying STING-mediated immune responses. When combined with anti-PD-1, the nanoparticle significantly inhibits tumor growth and liver metastasis. Collectively, BR@CuM@CM synergistically modulates metabolism and immune signaling to convert immunologically "cold" tumors into "hot" tumors, demonstrating translational potential to overcome immunotherapy resistance in CRC.