Integrating cuproptosis and immunosenescence: A novel therapeutic strategy in cancer treatment

Abstract

Recent advancements in our understanding of cell death mechanisms have progressed beyond traditional apoptosis to encompass various forms of regulated cell death, notably cuproptosis. This copper-dependent cell death occurs when copper interacts with lipoylated enzymes in the tricarboxylic acid cycle, leading to protein aggregation and subsequent cell death. Alongside this, immunosenescence the gradual decline in immune function due to aging has emerged as a significant factor in cancer progression and response to treatment. Innovative strategies that integrate cuproptosis and immunosenescence are showing considerable promise in cancer therapy. By leveraging the altered copper metabolism in cancer cells, cuproptosis can selectively induce cell death, effectively targeting and eliminating tumors. Simultaneously, addressing immunosenescence can rejuvenate the aging immune system, enhancing its capacity to identify and destroy cancer cells. This dual approach creates a synergistic effect, optimizing therapeutic efficacy by directly attacking tumor cells while revitalizing the immune response. Such integration bolsters the defense against cancer progression and recurrence and holds great potential for advancing cancer treatment modalities and improving patient outcomes. This paper delves into the interactions between cuproptosis and immunosenescence, emphasizing their implications for developing innovative cancer therapies.

Keywords: Cancer; Cuproptosis; Immunosenescence; Regulated cell death; Therapeutic resistance.

Graphical abstract

Fig. 1

Schematic model of cuproptosis illustrating the mechanism by which elesclomol binds extracellular copper (Cu²⁺) and transports it into intracellular compartments. Increased Cu accumulation leads to cuproptosis primarily through FDX1-mediated mitochondrial proteotoxic stress. FDX1 (Ferredoxin 1) reduces Cu²⁺ to Cu⁺, promoting the lipoylation and aggregation of mitochondrial enzymes like DLAT involved in the TCA cycle while destabilizing Fe–S cluster proteins. Additionally, Cu importers (e.g., SLC31A1) and exporters (e.g., ATP7B) regulate cuproptosis sensitivity by modulating intracellular Cu⁺ levels. The solid orange circles in the TCA cycle represent metabolites relevant to the lipoic acid pathway. Abbreviations: DLAT (dihydrolipoamide S-acetyltransferase), FDX1 (ferredoxin-1), Fe–S (iron-sulfur), LIAS (lipoic acid synthetase), TCA (tricarboxylic acid).

Fig. 2

Immunosenescence-related alterations in different immune cell subsets.

Fig. 3

Mechanisms of copper targeting and its potential applications in cancer therapy. Copper ionophores, transporters, and chelators play crucial roles in regulating cellular copper levels. Elevated copper concentrations can influence various biological processes, including promoting tumor growth and angiogenesis. Additionally, high copper levels can induce cell death through mechanisms such as cuproptosis, apoptosis via reactive oxygen species (ROS) elevation, and pyroptosis by activating inflammasomes and caspase-1. Furthermore, modulating copper levels can enhance treatment efficacy by sensitizing cancer cells to chemotherapy and radiotherapy, primarily by increasing oxidative stress and inhibiting DNA repair mechanisms.

Fig. 4

Interplay Between Cuproptosis and Immunosenescence in Cancer Progression. The left side illustrates cuproptosis, depicting copper ions (Cu²⁺) entering cancer cells and causing mitochondrial damage, ultimately leading to cell death. The right side shows aging immune cells, including T-cells and macrophages, highlighting their decline in function and the resultant increase in cancer progression. Central arrows demonstrate the feedback loop between cuproptosis and immunosenescence, emphasizing how copper-induced stress can exacerbate immune aging, while aging immune cells may further contribute to copper toxicity. This figure underscores the complex interactions between these two processes and their implications for cancer therapy. Created with the assistance of AI.