Hepatocellular carcinoma (HCC) relapse following incomplete microwave ablation (iMWA) represents a formidable clinical challenge. This progression is fueled by residual tumor cells that exhibit cell death resistance and dysregulated fatty acid metabolism, while exploiting a myeloid-derived immunosuppressive microenvironment. To address this limitation, we developed an injectable binary-amplified cascade hydrogel (S/CuCo@HD) that co-delivers CD36 inhibitor sulfosuccinimidyl oleate (SSO) and a copper–cobalt bimetal–organic framework (Cu–Co BMF). Locally administered S/CuCo@HD serves as a reservoir for sustained-release SSO and Cu–Co BMF within tumor cavities post-iMWA, provoking self-reinforced lipid oxygen radical storm by collaborative SSO-mediated fatty acid composition rewiring and peroxidase-mimetic Cu–Co BMF catalysis. The binary amplified radical reaction together with Cu2+-triggered cuproptosis culminates in a binary-amplified mitochondria crisis and subsequent the cytosolic release of damaged DNA fragments. Critically, these danger signals function as a pivotal immunological switch, sequentially initiating binary-amplified STING activation with Co2+ potentiation while simultaneously inducing robust ICD. The consequent release of damage-associated molecular patterns and interferon-β promotes dendritic cell maturation, polarizes macrophages toward an M1 phenotype, and facilitates T-cell infiltration, ultimately reprogramming the immunosuppressive microenvironment into an immune-activated niche. Crucially, S/CuCo@HD synergizes with anti-PD-1 therapy to reinvigorate cytotoxic T lymphocytes and establish durable immune memory, effectively suppressing tumor relapse and metastasis post-iMWA, offering an integrated metallo-metabolic-immunomodulation strategy with promising translational potential for comprehensive HCC management.
Liu et al. (Mon,) studied this question.