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

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

  • Adv Sci (Weinh). 2026 May;13(25):e15367. doi: 10.1002/advs.202515367.
Shaoqing Huang 1 2,  Shiyao Song 3,  Xinhua Zhang 1,  Jialing Gao 4,  Ruihan Pu 5,  Jiatong Dai 3,  Xiaoxue Wu 4,  Lulu Chen 4,  Qinghai Li 1,  Xiaoting Liu 6,  Qi Zhou 2 7,  Mei Song 1 4,  Weiling He 1 8
Affiliations

Affiliations

  • 1 Center for Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 2 Center for Hepato-Pancreatico-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 3 Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 4 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 5 School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 6 Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 7 Department of General Surgery, Hui Ya Hospital of The First Affiliated Hospital, Sun Yat-sen University, Huizhou, Guangdong, China.
  • 8 Department of Gastrointestinal Surgery, School of Medicine, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China.
PMID: 41722054 DOI: 10.1002/advs.202515367
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.

Keywords

PD‐L1; cancer; cuproptosis; disulfidptosis; integrated stress response (ISR); nanoparticles.

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