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

ABSTRACT 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.