Cuproptosis and Disulfidptosis Converge to Empower PD-L1 Checkpoint Therapy via Cadict-Induced PD-L1 Translation

Area of Science:

• Oncology
• Nanomedicine
• Immunotherapy

Background:

• Immune checkpoint blockade (ICB) is a key cancer therapy, but its efficacy is limited in tumors with low PD-L1 expression.
• Developing strategies to overcome resistance to ICB is crucial for improving patient outcomes.

Purpose of the Study:

• To develop a novel nanodrug (Cadict) that co-induces cuproptosis and disulfidptosis.
• To enhance tumor cell killing and sensitize PD-L1-low cancers to anti-PD-L1 therapy.

Main Methods:

• Cadict nanodrug utilizes copper-sulfur (Cu-S) coordination chemistry for co-delivery of copper ions and cystine.
• Integrates glucose oxidase (GOx) to induce a hypoglycemic environment for disulfidptosis.
• Targets epidermal growth factor receptor (EGFR) for precise delivery.

Main Results:

• Cadict co-induces cuproptosis and disulfidptosis, leading to synergistic tumor cytotoxicity.
• The dual-induction triggers an immunogenic cell death-like phenotype and activates the integrated stress response (ISR).
• ISR activation promotes PD-L1 upregulation, enhancing sensitivity to anti-PD-L1 therapy, resulting in tumor regression and immunological memory.

Conclusions:

• Cadict offers a novel strategy to overcome ICB resistance by targeting tumor redox vulnerabilities.
• This approach synergistically enhances anti-PD-L1 therapy efficacy through dual cell death induction and immune modulation.
• Represents a new paradigm for advancing cancer immunotherapy by sensitizing tumors to ICB.