Rewiring Metal-Dependent Cell Death to Unlock Immunotherapy in Colorectal Cancer

Area of Science:

• Oncology
• Immunology
• Materials Science
• Nanotechnology

Background:

• Immune checkpoint blockade (ICB) has limited success in colorectal cancer (CRC), especially in microsatellite-stable tumors with "cold" immune microenvironments.
• High copper and iron metabolism in CRC, linked to PD-L1 upregulation, suggests targeting cuproptosis and ferroptosis could improve ICB response.

Purpose of the Study:

• To develop a laser-activated lipid nanoplatform (CuFeS2-CA-DAC-Lipo, CCDL) to induce multimodal cell death and remodel the tumor immune microenvironment.
• To investigate CCDL's potential to enhance ICB responsiveness in colorectal cancer.

Main Methods:

• Utilized a CuFeS2-based lipid nanoplatform (CCDL) as a near-infrared II photothermal transducer and source of copper/iron ions.
• Administered decitabine to restore gasdermin E expression and chlorogenic acid to repolarize tumor-associated macrophages.
• Evaluated the induction of cuproptosis, ferroptosis, pyroptosis, and immune microenvironment modulation.

Main Results:

• CCDL induced concurrent cuproptosis and ferroptosis via ion overload and pyroptosis by coupling oxidative stress with caspase-3 activation.
• Chlorogenic acid effectively repolarized tumor-associated macrophages to a pro-inflammatory phenotype.
• The multimodal cell-death cascade created an immunogenic circuit that suppressed tumor growth and sensitized CRC to ICB.

Conclusions:

• The developed nanoplatform orchestrates a coordinated multimodal cell-death cascade, effectively remodeling the tumor immune microenvironment.
• This strategy shows promise in enhancing ICB efficacy and eliciting systemic antitumor immunity in colorectal cancer.
• CCDL represents a novel therapeutic approach for overcoming resistance to ICB in CRC.