From mechanism to application: programmed cell death pathways in nanomedicine-driven cancer therapies

Abstract

Programmed cell death (PCD) plays a crucial role in preventing cancer initiation and progression. Among the diverse PCD pathways, cuproptosis, pyroptosis, and ferroptosis have garnered attention for their unique mechanisms, which not only directly eliminate tumor cells but also enhance anti-tumor immunity. However, the therapeutic efficacy of PCD inducers is often compromised by rapid compensatory pathways in tumor cells, accelerated drug metabolism, and a lack of specificity, which can result in severe side effects. Engineered nanomedicines offer distinct advantages by leveraging nanoscale physicochemical properties to optimize pharmacokinetics, efficacy, and safety in cancer therapy. These nanomedicines enable precise targeting of tumor cells while enhancing drug stability. Moreover, they can simultaneously activate multiple PCD pathways and integrate with conventional therapies to further amplify anti-tumor effects. This review systematically examines the pathophysiological roles, mechanisms, and therapeutic implications of cuproptosis, pyroptosis, and ferroptosis in cancer treatment, with an emphasis on their modulation by nanomedicines. It also explores the potential interactions among these PCD pathways and highlights recent advancements in nanomedicine-based combination therapies targeting multiple PCD mechanisms. Finally, the challenges, limitations, and prospects for the clinical translation and application of PCD-targeting nanomedicines are discussed.

Keywords: Biomaterial; Cuproptosis; Ferroptosis; Nanomedicine; Programmed cell death; Pyroptosis.

Graphical abstract

Fig. 1

Chronology of the discovery of various PCD types. Created in BioRender. Zhang, Z. (2025) https://BioRender.com/a1uy4vz.

Fig. 2

This review aims to thoroughly explore the mechanisms of ferroptosis, cuproptosis, and pyroptosis (three prominent forms of PCD) in tumor therapy, providing a theoretical foundation for identifying potential therapeutic targets and offering guidance for the design and development of PCD-targeting nanomedicines. Created in BioRender. Zhang, Z. (2025) https://BioRender.com/ldqrajb.

Fig. 3

Schematic of cuproptosis mechanism. The copper ionophores ES/DSF sends Cu²⁺ into the cells and then into the mitochondria. Cu²⁺ is reduced to Cu⁺, inducing proteotoxic stress via protein lipoylation and subsequent DLAT aggregation. Moreover, Cu⁺ inhibits Fe-S cluster proteins formation, inducing cuproptosis. Created in BioRender. Zhang, Z. (2025) https://BioRender.com/e66j274.

Fig. 4

Schematic illustration of the DMMA@Cu_2-xSe nanosystem for cuproptosis-driven enhancement of thermotherapy. Reprinted with permission [76]. Copyright 2023, John Wiley and Sons.

Fig. 5

A) The preparation process of ECPCP. B) Schematic diagram of PEG@Cu₂O-ES inducing cuproptosis in breast cancer. Reprinted with permission [23,56]. Copyright 2024, John Wiley and Sons. Copyright 2024, Elsevier.

Fig. 6

A) Schematic illustration of the fabrication process of BCMD. B) Schematic illustration of the preparation process of Cel-Cu NP. C) Schematic illustration of HCu nanowires. Reprinted with permission [[87], [88], [89]]. Copyright 2023, Elsevier. Copyright 2024, John Wiley and Sons. Copyright 2024, John Wiley and Sons.

Fig. 7

Illustration of the mechanisms of the canonical pathway, non-canonical pathway, caspase-3/8 pathway, granzyme pathway, and gasdermin-mediated other pathways. Created in BioRender. Zhang, Z. (2025) https://BioRender.com/rdy3rde.

Fig. 8

A) The schematic illustration of the MPNPs preparation. B) Illustration showing the mechanisms that MPZPs induced pyroptosis and anti-tumor immunotherapy. Reprinted with permission [195]. Copyright 2023, John Wiley and Sons.

Fig. 9

Illustration shows that the disorder of lipid metabolism and iron metabolism in cells induces the accumulation of lipid peroxide and ferroptosis, and the cells prevent ferroptosis by producing reducing substances. Created in BioRender. Zhang, Z. (2025) https://BioRender.com/q45f149.

Fig. 10

A) Synthesis and biodegradation process of Fe₃O₄@PCBMA-SIM nanomedicine. B) Schematic diagram of ferroptosis induced by Fe₃O₄@PCBMA-SIM. Reprinted with permission [252]. Copyright 2021, Springer Nature.

Fig. 11

A) Synthesis process of ATO/SRF@BSA nanomedicine. B) A schematic diagram illustrates the mechanisms of ferroptosis induced by ATO/SRF@BSA. C) TEM images of mitochondria of 4T1 cells after receiving different administrations (scale bar = 500 nm). Reprinted with permission [254]. Copyright 2024, Elsevier.

Fig. 12

A) The preparation process of CQG NPs. B) A schematic illustration depicting the synergistic anticancer effects of cuproptosis and pyroptosis triggered by CQG NPs. Reprinted with permission [280]. Copyright 2023, John Wiley and Sons.

Fig. 13

A) The preparation process of MetaCell. B) A schematic illustration depicting the synergistic anticancer effects of cuproptosis and ferroptosis triggered by MetaCell. Reprinted with permission [79]. Copyright 2024, American Association for the Advancement of Science.

Fig. 14

Crosstalk among ferroptosis, pyroptosis, and cuproptosis pathways. Created in BioRender. Zhang, Z. (2025) https://BioRender.com/c5c7bnw.