Malignant tumors remain a leading cause of premature death worldwide, with disproportionately increasing burdens in resource-limited regions. Although immune checkpoint blockade (ICB) has emerged as a transformative cancer therapy, its efficacy is often limited by the immunosuppressive tumor microenvironment (TME). Leveraging iron as the most abundant bioactive transition metal in Earth’s crust, we report F-Fe, a complex IV-targeted carbon monoxide-releasing molecule (CORM) that is activated by a clinically approved dental light-curing unit to induce pyroptosis for reprogramming the TME. We developed a bioinspired delivery system named GLEAM to facilitate clinical applications that adhere to tissue surfaces while channeling light into deeper tissue for on-target CO release, simultaneously providing real-time visual feedback for treatment monitoring. Murine oral and breast cancer models validated the therapeutic efficacy, showing significant tumor suppression and TME remodeling. When combined with αPD-1 therapy, it markedly suppressed metastasis, prevented recurrence, and prolonged survival. Our findings suggest that Fe-based small molecules with biomimetic delivery can leverage dental light to boost ICB efficacy, offering a sustainable and translational approach to tumor treatment.
Wang et al. (Fri,) studied this question.