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Acquired radioresistance limits effective radiotherapy. Cuproptosis is a copper-dependent form of cell death driven by mitochondrial copper accumulation and lipoylated protein aggregation. Building on evidence that radioresistant cancer cells exhibit increased cuproptosis susceptibility, here we combine a radiation-responsive, copper-incorporated covalent organic framework (COF‑Tpy‑Se‑Cu) with an oncolytic adenovirus to target this vulnerability. X-ray irradiation triggers copper release from COF‑Tpy‑Se‑Cu and induces FDX1-dependent cuproptosis, while the oncolytic adenovirus depletes intracellular glutathione and stabilizes FDX1 by limiting its mitochondrial protease-mediated degradation. The combination enhances tumor cell death and remodels the immunosuppressive tumor microenvironment into a T-cell-inflamed state. In models of radioresistant tumors in female mice, this regimen improves tumor control and elicits CD8⁺ T cell-dependent systemic antitumor immunity and durable immunological memory. These findings support the combined use of radiation-responsive copper delivery and oncolytic virotherapy as a strategy for exploiting cuproptosis susceptibility and improving radiotherapy responses.