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

Immune checkpoint blockade (ICB) has emerged as a cornerstone of cancer therapy, yet its effectiveness remains restricted in PD-L1-low malignancies due to insufficient target expression. We herein develop the cuproptosis and disulfidptosis co-delivery targeted (Cadict) nanodrug, an epidermal growth factor receptor (EGFR)-targeted nanoplatform designed to co-induce cuproptosis and disulfidptosis, thereby synergistically augmenting tumor cytotoxicity and sensitizing cancers to anti-PD-L1 therapy. Cadict exploits copper-sulfur (Cu-S) coordination chemistry to co-deliver copper ions and cystine, while integrating glucose oxidase (GOx) to create a hypoglycemic milieu essential for disulfidptosis execution. This dual cytotoxic mechanism not only triggers immunogenic cell death-like phenotype but also unexpectedly activates the integrated stress response (ISR), promoting PD-L1 upregulation through Eif5b-dependent translation. The resulting synergy between redox-driven cytotoxicity and immune modulation potentiates anti-PD-L1 efficacy, leading to robust tumor regression and durable immunological memory. Our work presents a seminal strategy that leverages tumor redox vulnerabilities to advance cancer immunotherapy, providing a new paradigm for overcoming ICB resistance via targeted tumor sensitization.