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Cuproptosis enters the immunogenic cell death club

Guido Kroemer , Daolin Tang

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Vita > Cutting Edge > DOI: 10.15302/vita.2026.08.0061
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Cuproptosis enters the immunogenic cell death club

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The failure of purely cytotoxic cancer therapies has taught us that the immune system is the ultimate determinant of therapeutic success. Immunogenic cell death (ICD) is the process by which dying tumor cells activate adaptive anticancer immunity. In a recent Cell paper, Lei et al. show that cuproptosis is a potent inducer of ICD and that its combination with PD-L1 blockade promotes tumor rejection and overcomes resistance.

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The founding intuition of cytotoxic oncology — that sufficiently activating a cell-autonomous death program would cure cancer — has failed its most stringent test: durable disease control. Tumors may shrink because malignant cells are directly poisoned, yet lasting therapeutic success generally requires the host to be mobilized against residual and disseminated disease. Effective chemotherapy, radiotherapy and targeted therapy therefore work not only by reducing tumor mass, but also by generating antigens, inflammatory signals and an immune-permissive microenvironment that enable anticancer immunity1.
Immunogenic cell death (ICD) operationalizes this principle2. ICD is a functionally defined form of regulated cell death that is sufficient to elicit adaptive immunity against antigens expressed by dying cells. It is not a single morphological pathway. Rather, immunogenicity emerges from coordinated antigenicity and adjuvanticity, including calreticulin (CRT) exposure, adenosine triphosphate (ATP) secretion, high-mobility group box 1 (HMGB1) release and type I interferon (IFN) signaling, followed by dendritic-cell (DC) uptake, maturation, cross-presentation and T-cell priming. Apoptosis becomes immunogenic when coupled to the integrated stress response and, in many settings, viral mimicry. Necroptosis can be immunogenic when inflammatory execution is appropriately connected to antigen presentation1. Ferroptosis may also stimulate immunity, although extracellular glutathione peroxidase 4 (GPX4) released by ferroptotic cells can engage zona pellucida glycoprotein 3 (ZP3) on DCs for optimizing the presentation of tumor antigens to T cells3. Thus, the modality of death matters less than the molecular dialogue established with the immune system1.
Cuproptosis now joins this repertoire, as reported in a landmark paper in Cell by Lei et al4. In the context of cuproptosis, excess intracellular copper binds lipoylated mitochondrial proteins, promotes their aggregation and depletes iron-sulfur-cluster proteins, producing proteotoxic stress in a ferredoxin 1 (FDX1)-dependent metabolic context5,6. Lei et al. provide unusually comprehensive evidence that this process can constitute ICD (Fig. 1)4. Earlier studies also revealed that cuproptotic cell death exhibits greater immunogenicity than other cell death modalities3. Elesclomol-copper was more effective in immunocompetent than immunodeficient mice. Cuproptotic cells exposed CRT and released ATP, HMGB1 and IFNβ. Most importantly, vaccination with cuproptotic cancer cells protected mice against a subsequent challenge with living tumor cells, the defining in vivo test of ICD. Cuproptosis increased mature intratumoral dendritic cells, expanded conventional DC type 1 (cDC1) in tumor-draining lymph nodes, enhanced cross-presentation, and generated antigen-specific CD8+ T cells; DC depletion weakened both T-cell priming and tumor control4.
The conceptual advance extends beyond adding another death modality to the ICD catalogue. Lei et al. uncover a bidirectional amplification circuit. CD8+ T cells secrete IFNγ, which activates signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 1 (IRF1) in cancer cells; IRF1 directly drives FDX1 transcription, reinforcing protein lipoylation, mitochondrial oxidative metabolism and susceptibility to cuproptosis. Genetic loss of STAT1, IRF1 or FDX1, as well as CD8+ T-cell depletion or IFNγ neutralization, interrupted this circuit. Conversely, cuproptosis remodeled the tumor microenvironment toward dendritic-cell activation, a higher M1-like/M2-like macrophage ratio and stronger T-cell effector functions4.
This feedback loop creates an obvious therapeutic partner: programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blockade. Cuproptosis increased PD-L1, consistent with adaptive immune resistance. Anti-PD-L1 released this brake, increased IFNγ, IRF1, and FDX1, and amplified biochemical hallmarks of cuproptosis. Combination treatment was synergistic in immunogenic models and restored control in tumors with intrinsic or acquired resistance to checkpoint blockade4 (Fig. 1). This principle accords with earlier work combining disulfiram-associated copper stress with PD-L1 inhibition in non-small-cell lung cancer7, and with independent evidence that copper treatment induces ICD and improves PD-L1 blockade in lung cancer models8.
Altogether, these studies provide preclinical evidence indicating that cuproptosis inducers behave like other ICD inducers with respect to their capacity to sensitize tumors to immune checkpoint inhibitors (ICIs)9. Clinically, the benefit of combining ICD-inducing therapies with PD-1/PD-L1 blockade has been illustrated in several settings: anthracyclines in triple-negative breast cancers, oxaliplatin-based regimens in colorectal cancer, lurbinectedin in small-cell lung cancer, and anticancer antibody–drug conjugates whose payloads can trigger ICD and enhance the efficacy of ICIs in solid tumors1,10.
The identification of cuproptosis as an ICD modality widens our therapeutic armamentarium. Future work should define the damage-associated molecular pattern (DAMP) spectrum specific to cuproptosis, identify predictive biomarkers, including FDX1 and copper-metabolism signatures, and test cuproptosis inducers, alone or with ICIs, in the clinic. A key unresolved question is whether the immunogenicity of cuproptosis is an intrinsic consequence of its unique copper-dependent execution mechanism or is instead determined by the cellular and tumor-microenvironmental contexts in which cuproptosis occurs. The message is simple but profound: we do not cure cancer by killing it; we cure it by teaching the immune system to finish the job.

[1]

Galluzzi, L., Kepp, O., Zitvogel, L., Tang, D.L. & Kroemer, G. Cancer Cell 44, 281–305 (2026).

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Galluzzi, L., Guilbaud, E., Schmidt, D., Kroemer, G. & Marincola, F.M. Nat. Rev. Drug Discov. 23, 445–460 (2024).

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Liu, J. et al. Cell 189, 1056–1073.e24 (2026).

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Lei, G. et al. Cell https://doi.org/10.1016/j.cell.2026.05.036 (2026).

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Tang, D.L., Kroemer, G. & Kang, R. Nat. Rev. Clin. Oncol. 21, 370–388 (2024).

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Guo, Z.Y. et al. Signal Transduct. Target. Ther. 10, 149 (2025).

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Chen, J.Q. et al. Eur. J. Pharmacol. 1030, 179166 (2026).

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Pfirschke, C. et al. Immunity 44, 343–354 (2016).

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Kepp, O. & Kroemer, G. Oncoimmunology 14, 2584898 (2026).

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The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

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Kroemer, G., Tang, D.  Cuproptosis enters the immunogenic cell death club  Vita https://doi.org/10.15302/vita.2026.08.0061 ()
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