Engineering metal-non-metal asymmetric dual-atom catalyst for disulfidptosis-mediated potent immunotherapy.
The Co/Se DAC strategy shows promise in enhancing disulfidptosis and immune response for cancer therapy, achieving significant tumor growth suppression in vivo.
Where it sits
this study against the rest of the cjc-1295 with dac corpusSummary and findings
The study investigates a metal-non-metal asymmetric dual-atom catalyst (Co/Se DAC) to enhance disulfidptosis, a form of immunogenic cell death, for cancer therapy. The Co/Se DAC was loaded with 3-bromopyruvic acid and hyaluronic acid to target tumor cells, resulting in 93% suppression of primary tumor growth in vivo. The therapy also triggered immune responses, inhibiting distant tumor growth and metastasis.
Abstract
Disulfidptosis, a novel form of immunogenic cell death triggered by intracellular disulfide stress, presents a promising avenue for cancer therapy. However, it is severely constrained by the low efficacy of disulfide homeostasis disruption. Herein, a powerful energy metabolism regulation strategy targeting nicotinamide adenine dinucleotide phosphate (NADPH) was proposed that leveraged a metal-non-metal (Co/Se) asymmetric dual-atom catalyst (DAC) to amplify disulfidptosis for potent immunotherapy. Experimental and theoretical analyses revealed that the asymmetric Co/Se pair altered the electronic structure with the upshifted d-band center of the Co active center, resulting in stronger substrate adsorption and charge transfer properties, endowing the DAC with stronger NADPH oxidase (NOx)-like activity to achieve a remarkable enhancement in NADPH depletion. After loading with the glycolysis inhibitor 3-bromopyruvic acid (3-BP) and capping with hyaluronic acid (HA), the obtained Co/Se DAC-3-BP@HA efficiently targeted tumor cells. Co/Se DAC and 3-BP were liberated upon internalization, reversing the energy metabolism pathway and catalyzing the depletion of NADPH, causing severe disulfide stress. This further induced the co-activation of apoptosis and disulfidptosis, showing a 93% suppression of primary tumor growth in vivo. More importantly, the disulfidptosis-mediated therapy robustly triggered an immune response, as evidenced by the maturation of dendritic cells and the phenotype transformation of tumor-associated macrophages from M2 to M1, ultimately resulting in significant inhibition of distant tumor growth and pulmonary metastasis. This work not only provides a novel strategy to initiate potent disulfidptosis-mediated immunotherapy using asymmetric DAC, but also establishes a general paradigm for targeting energy metabolism to enhance immunotherapeutic effect.
Background
The study addresses the challenge of enhancing the efficacy of disulfidptosis, a form of immunogenic cell death, for cancer therapy. Disulfidptosis is limited by low efficacy in disrupting disulfide homeostasis, which is crucial for its therapeutic potential. This research is significant as it explores a novel strategy to amplify disulfidptosis using a dual-atom catalyst, potentially improving cancer immunotherapy outcomes.
Methods
The study utilized a metal-non-metal asymmetric dual-atom catalyst (Co/Se DAC) to target NADPH, enhancing disulfidptosis. The Co/Se DAC was loaded with the glycolysis inhibitor 3-bromopyruvic acid (3-BP) and capped with hyaluronic acid (HA) to target tumor cells. The experimental model involved in vivo testing for primary tumor growth suppression and immune response activation.
Results
The primary finding was a 93% suppression of primary tumor growth in vivo. The Co/Se DAC demonstrated enhanced NADPH depletion due to its NOx-like activity, leading to severe disulfide stress and co-activation of apoptosis and disulfidptosis. The therapy also triggered immune responses, including dendritic cell maturation and macrophage phenotype transformation, significantly inhibiting distant tumor growth and pulmonary metastasis.
Interpretation
The results suggest that the Co/Se DAC strategy significantly enhances disulfidptosis and immune response, offering a promising approach for cancer therapy. However, the clinical significance of these findings is uncertain without human data. The study's reliance on in vivo models limits the direct applicability of the results to human patients.
Key findings
- 93% suppression of primary tumor growth in vivo.
- Co/Se DAC altered electronic structure with upshifted d-band center.
- Enhanced NADPH depletion due to stronger NOx-like activity.
- Induced co-activation of apoptosis and disulfidptosis.
- Significant inhibition of distant tumor growth and pulmonary metastasis.
Limitations
- Not reported in abstract.