Recent advances in copper sulfide nanoparticles for cancer diagnosis and therapy

Abstract

Cancer, a highly heterogeneous and complex disease characterized by multiple genetic and metabolic abnormalities, remains one of the leading causes of death worldwide. Although conventional treatments such as surgery, chemotherapy, and radiotherapy, can mitigate the disease to some extent, their efficacy remains constrained by various factors. In recent years, nanotechnology has emerged as a promising approach for cancer treatment, with copper-based nanomaterials garnering significant attention due to their unique physicochemical properties and favorable biocompatibility. Copper sulfide (CuS) nanomaterials, in particular, have shown great potential as a versatile platform for both diagnosis and therapy, primarily due to their superior photothermal properties. Moreover, copper plays a crucial role in tumorigenesis, progression, and multiple cell death pathways, further highlighting its potential in cancer therapy. This review discusses the metabolic regulation of copper and its diverse roles in tumor biology, examines the applications and recent advances of CuS nanomaterials in cancer therapy, and explores their future potential in cancer diagnosis and treatment.

Keywords: Copper sulfide nanomaterials; Cuproptosis; Multimodal combination therapy; Nanomedicine; Photothermal therapy.

Graphical abstract

Fig. 1

Schematic representation of intracellular copper metabolism. During cellular copper uptake, Cu²⁺ is first reduced to Cu ⁺ by the STEAP family of proteins on the cell membrane, after which Cu⁺ is transported into the cytoplasm via SLC31A1. Additionally, Cu²⁺ can also be directly transported across the membrane by the divalent metal transporter DMT1. In the cytoplasm, Cu⁺ is typically bound by specific chaperone proteins to prevent toxicity and ensure proper intracellular distribution. Within mitochondria, COX17 mediates the transfer of Cu⁺ to the inner mitochondrial membrane, where it is delivered to cytochrome c oxidase (CCO) through SCO1 or COX11, supporting the electron transport chain and associated redox reactions. Meanwhile, FDX1 catalyzes the reduction of Cu²⁺ to Cu⁺, which plays a crucial role in cuproptosis. In the nucleus, histones H3 and H4 possess reductase activity, facilitating the reduction of Cu²⁺ to Cu⁺ and regulating gene expression. Additionally, in the trans-Golgi network (TGN), ATP7A/B is responsible for the transport of Cu⁺. When intracellular copper levels rise, ATP7A/B translocates to the plasma membrane to facilitate copper efflux, thereby maintaining cellular copper homeostasis. Created with Figdraw.

Fig. 2

Schematic illustration of copper metabolism regulation within the tumor microenvironment and its carcinogenic mechanisms. Copper metabolism in tumors is distinctly regulated compared to normal cells, facilitating cancer cell proliferation, migration, drug resistance, and angiogenesis. (1) Enhanced copper uptake: Overexpression of the copper transporter SLC31A1 in various tumors increases extracellular Cu⁺ influx, elevating intracellular copper levels. (2) Promotion of proliferation and malignant transformation: Elevated intracellular copper activates PI3K/AKT and MAPK/ERK signaling pathways, driving cell cycle progression and abnormal proliferation. (3) Facilitation of invasion and metastasis: Copper upregulates HIF-1α and LOX, synergistically enhancing tumor metastasis. (4) Regulation of energy metabolism: Increased copper activates c-Myc, promoting transcription of GLUT1, PKM, and LDHA, and enhances CCO activity to regulate oxidative phosphorylation. (5) Angiogenesis promotion: Tumor hypoxia induces HIF-1α and NF-κB activation, upregulating VEGF, FGF, and ILs, thereby stimulating angiogenesis. (6) Drug resistance: Copper accumulation activates the β-catenin/TCF4 transcriptional complex, upregulating ATP7B expression to enhance copper efflux and tumor cell survival. Created with Figdraw.

Fig. 3

The role of copper in cancer cell death. Copper plays a critical role in cancer cell death by modulating multiple cell death mechanisms, including autophagy, apoptosis, pyroptosis, ICD, ferroptosis, and cuproptosis. Through regulation of redox balance, mitochondrial function, and key signaling pathways, copper can initiate or modulate cell death processes, ultimately influencing cancer cell survival and therapeutic responses. Created with Figdraw.

Fig. 4

Molecular mechanisms of cuproptosis. Cuproptosis is a form of copper ion (Cu²⁺/Cu⁺)-mediated cell death. Copper ion carriers (e.g., ES) mediate the transport of extracellular copper ions into mitochondria, where Cu²⁺ is reduced to Cu ⁺ by FDX1, resulting in intracellular Cu⁺ accumulation. Cu⁺ interacts with DLAT in the tricarboxylic acid (TCA) cycle, inducing protein aggregation. Additionally, FDX1-and LIAS-mediated protein lipoylation regulates mitochondrial protein aggregation and leads to the loss of Fe-S cluster proteins and inactivation of Npl4-p97, ultimately culminating in cell death. Copper transporters (e.g., SLC31A1 and ATP7A/B) modulate intracellular copper levels, thereby influencing cellular sensitivity to cuproptosis. Moreover, intracellular accumulation of GSH in tumor cells or the administration of exogenous copper chelators can inhibit cuproptosis, underscoring the critical role of copper homeostasis in regulating cell fate. Created with Figdraw.

Fig. 5

CuS nanoparticles for PET imaging. (A) Micro-PET/CT images of subcutaneous U87 glioma xenografts in nude mice at 1, 6, and 24 h after intravenous injection of PEG-⁶⁴CuCuS nanoparticles. Yellow arrowheads indicate tumors, orange arrowheads indicate bladders, and red arrowheads indicate standards. (A) Reprinted with permission from Ref. [138]. Copyright 2010, American Chemical Society. (B) PET/CT images of the pelvis using ⁶⁴CuCl₂ (B1) and ¹⁸F-choline (B2). (B) Reprinted with permission from Ref. [140]. Copyright 2018, SNMMI.

Fig. 6

CuS nanoparticles for PAI. (A) In vivo distribution of CuS nanoparticles in living mice post-injection monitored by PAI. (B) PAI of mouse blood vessels before and after CuS nanoparticle injection. (C) NIR-II PAI of subcutaneous prostate tumors in mice following injection of CuS or BBN-CuS nanoparticles. (A–C) Reprinted with permission from Ref. [145]. Copyright 2021, Royal Society of Chemistry. (D) Hematological and biochemical analyses following injection of CaCO₃@CuS/PDA nanoparticles. (E) Reconstructed PAI of the mouse brain post-injection of CaCO₃@CuS/PDA nanoparticles, including a time series at 30 and 330 s showing major blood vessels and fine microvessels, respectively. (D, E) Reprinted with permission from Ref. [146]. Copyright 2024, John Wiley and Sons. (F) PAI of RGD-CuS and CuS at varying copper concentrations. (F) Reprinted with permission from Ref. [147]. Copyright 2021, American Chemical Society.

Fig. 7

CuS nanoparticles for MRI/CT. (A) MRI of intracranial gliomas in rats following injection of Tf-DSF/CuS nanoparticles. (A) Reprinted with permission from Ref. [152]. Copyright 2021, Elsevier. (B) MRI of in situ HCC in SD rats on days 0, 3, 7, and 10 after transcatheter injection of DOX@BSA-CuS nanoparticles. (B) Reprinted with permission from Ref. [153]. Copyright 2021, Elsevier. (C) CT images of tumor sites at 0, 3, and 6 h post-intravenous injection of Bi₂O₃@CuS in 4T1 tumor-bearing mice. (C) Reprinted with permission from Ref. [154]. Copyright 2024, Oxford University Press. (D) SPECT/CT images of rats bearing in situ mammary tumors after injection of ¹³¹I-HCuSNPs-MS-PTX. (D) Reprinted with permission from Ref. [155]. Copyright 2018, Elsevier.

Fig. 8

CuS-based PTT. (A) T-MAN for fluorescence/MR dual-modality imaging and tumor-targeted PTT. (B) Photothermal stability of T-MAN after five cycles of laser irradiation in deionized water. (C) Cell viability evaluation of MKN45 and GES-1 cells with and without laser irradiation under different concentrations of T-MAN incubation conditions. (D) Infrared thermal imaging of subcutaneous MKN45 tumors in mice within 12 h after intravenous injection of T-MAN and laser irradiation for 0–5 min. (E) Dynamic changes in tumor volume in mice treated with different groups. A–E: Reprinted with permission from Ref. [169]. Copyright 2019, American Chemical Society. (F) Electrochemical synthesis process of CuS-Au nanohybrid materials and their application in phototherapy. (G) Cytotoxicity analysis of different concentrations of TSP-CA on A549 cells after laser irradiation. (H) Percentage of DCF fluorescence generated in treated cells, used to assess ROS levels. (I) Temperature change curves and infrared thermal images at different time points as TSP-CA concentration increases. F–I: Reprinted with permission from Ref. [170]. Copyright 2023, American Chemical Society.

Fig. 9

CuS-based PTT combined with CDT. (A) Schematic diagram of the construction of CD47@CCM-Lap-CuS nanoparticles and their mechanism of mediating PTT/CDT synergistic therapy for breast cancer. (B) Changes in UV–visible absorption spectra of TMB oxidation catalyzed by CD47@CCM-Lap-CuS NPs at different concentrations in the presence of 5 mM H₂O₂. (C) Comparison of cell viability of 4T1 cells in different treatment groups after 1064 nm laser irradiation. (D, E) Tumor growth curves and body weight changes of mice receiving different treatments. A–E: Reprinted with permission from Ref. [184]. Copyright 2023, American Chemical Society. (F) Schematic diagram of the construction process of PZTC/SS/HA nanocomplex and its in situ conversion to CuS under NIR-II laser irradiation to achieve photothermal effect and enhance CDT therapy. (G, H) Cell viability of HCT-116 and HEK-293K cells after 24 h of incubation with different doses of PZTC/SS/HA NCs. (I, J) Body weight changes and tumor weights of BALB/c nude mice in different treatment groups. F–J: Reprinted with permission from Ref. [185]. Copyright 2023, Elsevier.

Fig. 10

CuS-based PTT combined with PDT. (A) Schematic diagram of the construction of the dual-powered IR820@CuS/Pt nanomotor and its mechanism of action in deep tumor penetration, alleviating the hypoxic microenvironment, and synergistically achieving PDT and PTT treatment. (B) Cell viability evaluation of 4T1 cells after treatment with different nanoparticles. (C) Changes in viability of 4T1 cells after treatment with different concentrations of nanoparticles. (D) Body weight changes of mice under different treatment regimens. (E) Tumor growth curves of mice in different treatment groups. A–E: Reprinted with permission from Ref. [196]. Copyright 2023, Elsevier. (F) Comparison of the traditional FRET and dual-site FRET mechanisms of ApoE-ZCU nanoparticles, demonstrating their advantages in in situ brain glioma targeted phototherapy. (G) Cell viability analysis of U87 cells under different treatment methods. (H) Crystal violet staining images of U87 cells after different treatments. (I) Quantitative changes in tumor fluorescence signal intensity over time. (J) Survival curves of mice in different treatment groups. F–J: Reprinted with permission from Ref. [197]. Copyright 2023, American Chemical Society.

Fig. 11

CuS-based PTT combined with chemotherapy. (A) Schematic diagram of the construction of CuS@DMONs-FA-DOX-PEG nanoparticles and their mechanism of action in the synergistic anti-tumor effect of chemotherapy and PTT. (B) Release curve of DOX from nanoparticles. (C) Toxicity evaluation of different concentrations of nanoparticles on 4T1 cells under different treatment conditions. (D) Body weight changes of mice in each treatment group. (E) Changes of tumor volume of mice in each group over time. A–E: Reprinted with permission from Ref. [209]. Copyright 2024, Elsevier. (F) Schematic diagram of the synthesis process of CuS@DOX/CaO₂-HA and its application mechanism in enhancing the synergistic anti-tumor effect of chemotherapy/PTT. (G) Effects of different treatments on cytotoxicity under normoxic and hypoxic conditions at pH 6.5. (H) P-gp protein expression levels in HepG-2 cells after 6 h of treatment with CuS@DOX/CaO₂-HA under normoxic, aerobic, and hypoxic conditions. (I) Relative changes in tumor volume during treatment. (J) Body weight changes of mice in different treatment groups. F–J: Reprinted with permission from Ref. [214]. Copyright 2024, Elsevier.

Fig. 12

CuS-based PTT combined with RT. (A) Schematic diagram of the mechanism of LA-PEG-modified Cu_xS/Au nanoparticles for synergistic thermoradiotherapy. (B) Comparison of EMT-6 cell survival rates after treatment with PBS, Cu_xS/Au-PEG NPs, and Cu_xS/Au-PEG NPs + PTT at different X-ray doses. (C) Evaluation of the radiosensitization effect of each treatment group based on a multi-target single-shot model. (D) Curves of tumor volume changes in mice in different treatment groups. (E) Body weight changes of tumor-bearing mice in each group. A–E: Reprinted with permission from Ref. [233]. Copyright 2020, American Chemical Society. (F) Schematic diagram of the construction of the multifunctional CuS@CeO₂ nanoplatform. (G) Effects of different doses of radiation treatment on HepG2 cell viability in the presence or absence of CuS@CeO₂ nanoparticles. (H) Relative tumor volume and body weight changes in HepG2 tumor-bearing mice under different treatment regimens. F–H: Reprinted with permission from Ref. [234]. Copyright 2019, John Wiley and Sons.

Fig. 13

CuS-based PTT combined immunotherapy. (A) Schematic diagram of the construction process of the AM@DLMSN@CuS/R848 nanosystem and its synergistic mechanism for the treatment of TNBC through photothermal ablation combined with immune microenvironment remodeling. (B) Cytotoxicity evaluation of 4T1 cells treated with a CuS nanoparticle formulation combined with laser irradiation for 24 h. (C) Comparison of CRT levels in 4T1 cells after different treatments, used to assess ICD. (D) Volume growth curves of primary tumors in mice treated with different treatment groups. (E) Survival curves of mice in each group during treatment. A–E: Reprinted with permission from Ref. [238]. Copyright 2020, American Chemical Society. (F) Schematic diagram of the composition and structure of IL@H-PP and its mechanism of action in the treatment of primary breast cancer and brain metastasis. (G) Flow cytometric analysis of the ratio of CD206⁺ and CD80⁺ cells in IL-4-induced RAW cells after treatment with different agents, used to characterize the polarization state of macrophages. (H) Changes in tumor volume and body weight of mice in each treatment group. F–H: Reprinted with permission from Ref. [239]. Copyright 2023, Elsevier.

Fig. 14

CuS-based PTT combined with GT. (A) Schematic diagram of the construction of RGD-CuS DENPs and their synergistic application in PAI and PTT/GT therapy for tumors and metastases. After release from the nanocomplex, pDNA enters the cell nucleus and completes protein expression, thereby inhibiting cancer cell metastasis; DENPs also achieve photothermal ablation of cancer cells. (B) Western blot analysis of HIC1 protein expression levels in MDA-MB-231 cells treated with T/pDNA and NT/pDNA complexes. (C) Comparison of the survival rates of MDA-MB-231 cells treated with PBS, NT, and T under different copper concentrations and with or without laser irradiation. (D, E) Relative tumor volume and body weight changes in tumor-bearing mice during treatment under different treatment regimens. A–E: Reprinted with permission from Ref. [147]. Copyright 2021, American Chemical Society. (F) Design of a NIR-triggered CuS nanoplatform for delivering Cas9 RNP and DOX for combined PTT/GT therapy. (G) Surveyor enzyme digestion method was used to evaluate the insertion/deletion mutation frequency of CuS NPs and CuS-RNP@PEI in A375 cells with and without NIR irradiation. (H) Western blot analysis of the expression level of Hsp90α protein in tumor cells under different treatment conditions. (I) Analysis of off-target effects in tumor tissues treated with CuS-RNP@PEI combined with NIR. Mismatched bases are marked in red. F–I: Reprinted with permission from Ref. [248]. Copyright 2021, John Wiley and Sons.

Fig. 15

CuS-based PTT combined with multiple therapeutic modalities. (A) Schematic diagram of the multi-mechanism synergistic treatment of GBM initiated by cascade catalytic reactions using CTHG-Lf NPs. A: Reprinted with permission from Ref. [260]. Copyright 2023, Elsevier. (B) Schematic diagram of the construction process of the HMCuS@DOX@9R–P201 dual-responsive smart nanoplatform and its multi-modal synergistic treatment application in HCC. B: Reprinted with permission from Ref. [264]. Copyright 2024, Elsevier. (C) Schematic diagram of the preparation of CuS-PEI-siRNA-SFNs and its mechanism of action in the treatment of metastatic breast cancer, demonstrating its potential to significantly inhibit breast cancer metastasis through a quadruple treatment model. C: Reprinted with permission from Ref. [267]. Copyright 2024, Elsevier. (D) Schematic diagram of the construction process of the HMCuS/Pt/ICG@MnO₂@9R-P201 intelligent nanoplatform and its multimodal synergistic therapeutic mechanism for HCC. D: Reprinted with permission from Ref. [102]. Copyright 2025, Elsevier.