Copper homeostasis and copper-induced cell death in tumor immunity: implications for therapeutic strategies in cancer immunotherapy

Biomarker Research (2024) 12:130 Zhang et al. Biomarker Research https://doi.org/10.1186/s40364-024-00677-8 Open Access REVIEW Copper homeostasis and copper‑induced cell death in tumor immunity: implications for therapeutic strategies in cancer immunotherapy Suhang Zhang1,2,3†, Qibo Huang4†, Tuo Ji5, Qilin Li1,2,3* and Chuanyu Hu1,2,3* Abstract Copper is an important trace element for maintaining key biological functions such as cellular respiration, nerve conduction, and antioxidant defense. Maintaining copper homeostasis is critical for human health, and its imbalance has been linked to various diseases, especially cancer. Cuproptosis, a novel mechanism of copper-induced cell death, provides new therapeutic opportunities for metal ion regulation to interact with cell fate. This review provides insights into the complex mechanisms of copper metabolism, the molecular basis of cuproptosis, and its association with cancer development. We assess the role of cuproptosis-related genes (CRGs) associated with tumorigenesis, their importance as prognostic indicators and therapeutic targets, and the impact of copper homeostasis on the tumor microenvironment (TME) and immune response. Ultimately, this review highlights the complex interplay between copper, cuproptosis, and cancer immunotherapy. Keywords Copper homeostasis, Copper metabolism, Cuproptosis, Cancer immunotherapy † Suhang Zhang and Qibo Huang contributed equally to this work and are considered co-first authors. *Correspondence: Qilin Li Chuanyu Hu 1 Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China 2 School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China 3 Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430030, China 4 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China 5 School of Medicine, New York Medical College, Valhalla, NY 10595, USA Introduction Copper, an essential micronutrient, is intricately involved in a plethora of biological processes, including but not limited to, cellular respiration, neurotransmission, and antioxidant defense [1, 2]. Its quintessential role as a cofactor for a variety of enzymes underscores the delicate balance required for copper homeostasis within the human body. However, the perturbation of this balance has been implicated in a spectrum of pathological conditions, with cancer being a notable example where copper dysregulation is observed [3]. The discovery of cuproptosis, a copper-mediated form of regulated cell death, has opened new avenues in understanding the complex interplay between metal ion homeostasis and cell fate [4]. Cuproptosis presents a unique mechanism that is tightly regulated and can be harnessed for therapeutic purposes. The delineation of this novel cell death pathway has not only advanced our comprehension of copper’s role in © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhang et al. Biomarker Research (2024) 12:130 cellular physiology but also highlighted its potential as a target for cancer therapy [5]. While prior studies have shed light on the involvement of copper metabolism and deposition in tumorigenesis, the specific functions and mechanisms of copper metabolism within the TME, particularly in the context of tumor therapy and immunotherapy, remain unclear. The present review aims to consolidate recent research findings, explore the molecular mechanisms governing copper metabolism and deposition in cancer, evaluate the prognostic significance of CRGs in cancer patients, and investigate their role in influencing the immune response by affecting the TME, ultimately suggesting a new approach for cancer immunotherapy. Copper metabolism Copper metabolism is mainly accomplished through absorption, utilization, and excretion. Here, the Page 2 of 34 mechanisms of copper metabolism in the human body will be summarized (Fig. 1). Copper uptake The human body primarily obtains copper from the diet such as shellfish, nuts, and animal offal, which are a significant source of this essential mineral. The recommended daily copper intake for adults is 0.8–2.4 mg, with an average absorption rate of copper from food estimated to be 50% [6]. Copper is absorbed in the small intestine and transported to the portal vein by the ATPase copper transporting alpha (ATP7A), and then transferred to the liver through plasma proteins, albumin, and transferrin [7]. The liver serves as the primary organ responsible for the storage, distribution, and excretion of copper. Subsequently, copper enters the systemic blood circulation and is distributed to all tissues and cells. The absorption of copper is an intricate physiological process that facilitates the safe and effective uptake of this vital trace element Fig. 1 The mechanism of copper metabolism. The complex metabolic mechanism of copper helps to maintain its homeostasis. C u2+ can be transported by ZnT1, or Cu2+ is reduced to Cu+ by STEAP on the cell membrane and then transported into the cell by SLC31A1/CTR1. After entering the cell, copper is bound by different copper-binding proteins such as COX17, CCS, and ATOX1 for transportation to different organelles such as mitochondria and nucleus to play its role, and the excess free copper is stored by GSH and MT binding to protect the cell. Copper efflux is handled by ATP7A/B, which is localized on the trans Golgi network Zhang et al. Biomarker Research (2024) 12:130 from the diet and its subsequent delivery to the various cells and tissues in need. Copper in food predominantly exists in an inorganic form as copper salts, while within living organisms it is found as copper ions in both the reduced state (Cu+) and the oxidized state (Cu2+). Here we describe the molecular mechanisms (...truncated)