Targeting cuproptosis for cancer therapy: Focus on the anti-tumor immune system

Sep 22, 2026

Copper is a crucial micronutrient controlling signaling and cellular homeostasis, yet excess disrupts the tricarboxylic acid cycle, promotes fatty acylated protein accumulation, destabilizes iron–sulfur cluster proteins, and elevates reactive oxygen species, triggering proteotoxic stress and death. Cuproptosis is a Cu-dependent regulated cell death distinct from other RCD modes, first reported in 2022 and increasingly exploited in oncology. Because tumors often escape apoptosis, alternative cuproptosis-linked mechanisms are urgently explored. The review connects cuproptosis to anti-tumor immunity by linking copper-related genes, immune infiltration, PD-1/PD-L1, and stage-specific tumor immune microenvironment effects to guide drug development.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Introduction

Copper metabolism in disease and cancer

Cuproptosis as a Cu-dependent cell death pathway

Cuproptosis-related gene expression and immune infiltration

PD-1/PD-L1 and checkpoint integration

Therapeutic strategies targeting cuproptosis in cancer

Cancer Pathogenesis and Therapy 3 (2025) 226–243 Contents lists available at ScienceDirect Cancer Pathogenesis and Therapy journal [homepage:](homepage: www.journals.elsevier.com/cancer-pathogenesis-and-therapy)[ www.journals.elsevier.com/cancer-pathogenesis-and-therapy](homepage: www.journals.elsevier.com/cancer-pathogenesis-and-therapy) Review article Targeting cuproptosis for cancer therapy: Focus on the anti-tumor immune system☆ Xuan Zhang, Xiaohong Han * Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China H I G H L I G H T S A R T I C L E I N F O Managing Editor: Peng Lyu Keywords: Cuproptosis Copper homeostasis Immunotherapy Drug synergism G R A P H I C A L A B S T R A C T | | | --- | | | | A B S T R A C T | Copper (Cu) is an indispensable micronutrient that maintains signaling pathways and biological homeostasis in almost all cell types; however, its excess affects the tricarboxylic acid cycle, causes the accumulation of fatty acylated proteins, destabilization of iron–sulfur cluster proteins, and increases the levels of intracellular reactive oxygen species, leading to proteotoxic stress and cell death. Cuproptosis, a form of Cu-dependent cell death, differs from other types of regulated cell death (RCD) and was ﬁrst reported in Science in 2022. Recently, the RCD pathways have been targeted in cancer therapy. However, the escape of apoptosis in tumor cells causes resistance to treatment and tumor recurrence. Therefore, there is an urgent need to study the alternative mechanisms of cancer cell mortality. Compared to normal patients, a signiﬁcant increase in serum Cu ion levels has been observed in patients with tumors. Moreover, tumor cell proliferation, angiogenesis, and metastasis are associated with cuproptosis. Thus, exploring cancer signaling pathways related to cuproptosis will provide a new perspective for the development of anti-cancer drugs. Importantly, cuproptosis is closely associated with the modulation of ☆ Given her role as Editorial board member, Prof. Xiaohong Han had no involvement in the peer-review of this article and has no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to Managing Editor, Peng Lyu. * Corresponding author: Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China. E-mail [address:](address: hanxiaohong@pumch.cn)[ hanxiaohong@pumch.cn](address: hanxiaohong@pumch.cn) (X. Han). [https://doi.org/10.1016/j.cpt.2024.07.005](https://doi.org/10.1016/j.cpt.2024.07.005) Received 19 May 2024; Received in revised form 17 July 2024; Accepted 24 July 2024 2949-7132/© 2024 Published by Elsevier B.V. on behalf of Chinese Medical Association (CMA). This is an open access article under the CC BY-NC-ND license ([http://](http://)[ ](http://)[creativecommons.org/licenses/by-nc-nd/4.0/](creativecommons.org/licenses/by-nc-nd/4.0/)). X. Zhang, X. Han Cancer Pathogenesis and Therapy 3 (2025) 226–243 anti-tumor immunity. The expression of cuproptosis-related genes (CRGs) is signiﬁcantly correlated with immune cell inﬁltration and the immune checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1). Based on these ﬁndings, a series of cuproptosis-related drugs have been used in tumor-targeted combination therapy or as immune synergists. Ther

FAQs

What is cuproptosis and how is it triggered in cells?

Cuproptosis is a copper (Cu)-dependent form of regulated cell death. Excess Cu disrupts key cellular processes, leading to proteotoxic stress and cell death.

Why is cuproptosis considered important for cancer therapy?

Tumors can escape apoptosis, causing treatment resistance and recurrence. Targeting cuproptosis offers an alternative pathway linked to cancer cell mortality and progression.

How does cuproptosis relate to anti-tumor immune responses?

Cuproptosis-related genes correlate with immune cell infiltration and with the PD-1/PD-L1 immune checkpoint axis. The review discusses how these links may influence tumor prognosis and immunotherapy outcomes.

Sep 22, 2026

Upload by Theodora