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Hydrazide/Metal/Indocyanine Green Coordinated Nanoplatform for Potentiating Reciprocal Ferroptosis and Immunity
Guanghui Hou1,2, Junmin Qian1, Yaping Wang3
1State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an710049, P. R. China.
Abstract:
Ferroptosis holds great potential in cancer treatment, but its efficacy is severely limited by a low Fenton reaction efficacy. Meanwhile, the interactive relationship between Ferroptosis and the PD-1 blockade is still vague. Herein, a hydrazide/Cu/Fe/indocyanine green coordinated nanoplatform (TCFI) is constructed by a hydrazide-metal-sulfonate coordination process. The TCFI nanoplatform exhibits Fenton-/catalase-/glutathione oxidase-like triple activities and accordingly can trigger lipid peroxidation, relieve hypoxia, and downregulate the glutathione/glutathione peroxidase 4 axis, thus achieving positively and negatively dually enhanced Ferroptosis in B16F10 cancer cells. Under near-infrared laser irradiation, the TCFI nanoplatform induces robust immunogenic cancer cell death by elevating the intracellular reactive oxygen species level through synergistic photodynamic therapy/Ferroptosis, which significantly potentiates CD8+ T cell infiltration into tumors and interferon-γ secretion. Moreover, upregulated interferon-γ efficiently inhibits system xc- activity and sensitizes cancer cells to Ferroptosis. Interestingly, the PD-1 blockade may strengthen the reciprocal process. The combination of the TCFI nanoplatform and αPD-1 can eliminate primary tumors and inhibit distant tumor growth, lung metastasis, and tumor recurrence. This study presents a simple and novel coordination strategy to fabricate tumor microenvironment-responsive nanodrugs and highlights the enhancement effect of photodynamic therapy on reciprocal Ferroptosis and antitumor immunity.
Insights
This study introduces a novel nanoplatform (TCFI) that enhances ferroptosis (a cancer cell death pathway) and immune response. Combining TCFI with PD-1 blockade effectively eliminates tumors and prevents recurrence.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Ferroptosis shows promise for cancer treatment but is limited by low Fenton reaction efficiency.
- The interplay between ferroptosis and PD-1 blockade in cancer immunity remains unclear.
Purpose of the Study:
- To develop a novel nanoplatform (TCFI) for enhanced ferroptosis and synergistic cancer immunotherapy.
- To investigate the combined efficacy of TCFI and PD-1 blockade against tumors.
Main Methods:
- A hydrazide/Cu/Fe/indocyanine green coordinated nanoplatform (TCFI) was synthesized.
- TCFI demonstrated Fenton-, catalase-, and glutathione oxidase-like activities to induce dual ferroptosis.
- Synergistic photodynamic therapy and ferroptosis were employed to enhance immunogenic cancer cell death.
Main Results:
- TCFI triggered lipid peroxidation, relieved hypoxia, and downregulated the glutathione axis, enhancing ferroptosis in B16F10 cells.
- Near-infrared laser irradiation with TCFI induced immunogenic cell death, boosting CD8+ T cell infiltration and interferon-γ secretion.
- The combination of TCFI and αPD-1 effectively eliminated primary tumors, inhibited distant tumor growth, metastasis, and recurrence.
Conclusions:
- The developed TCFI nanoplatform offers a novel strategy for tumor microenvironment-responsive nanodrugs.
- Photodynamic therapy enhances ferroptosis and antitumor immunity, showing significant therapeutic potential.
- Combining TCFI with PD-1 blockade presents a potent strategy for comprehensive cancer treatment.
