Tumor-activated nanocomplex reprograms cancer and macrophage metabolism in opposite directions to overcome immune suppression

Immunotherapy efficacy is hindered by the immunosuppressive metabolism of cancer cells and tumor-associated macrophages (TAMs), yet their opposite metabolic programs complicate synchronized modulation of tumor microenvironment. Here, we report an acid-activated Fe–Zn nanocomplex (FZNC) that transforms into spiky FeOOH nanoparticles within the tumor microenvironment. This transformation enhances cellular uptake and enables selective scavenging of hydrogen sulfide (H₂S)—a metabolite that promotes glycolysis in cancer cells and oxidative phosphorylation (OXPHOS) in TAMs. Local H₂S depletion by FZNCs induces a bidirectional metabolic shift: cancer cells are redirected from glycolysis to OXPHOS, while TAMs switch from OXPHOS to glycolysis. This dual reprogramming enhances tumor immunogenicity with increased dendritic cell maturation and M1 polarization in vitro, and enhanced cytotoxic T-cell infiltration in vivo. FZNCs treatment suppresses tumor growth and metastasis, with synergistic effects when combined with PD-L1 blockade. This work introduces a materials-based strategy to spatially coordinate opposing metabolic programs for improved antitumor immunity.