Immunogenic Cell Death Mechanisms in Cancer Therapy

Immunogenic cell death (ICD) has emerged as a therapeutic paradigm in which regulated death pathways in malignant cells actively engage the immune system, transforming cytotoxic interventions into in situ vaccines. ICD is characterised by the orchestrated emission of damage-associated molecular patterns (DAMPs) such as surface-exposed calreticulin, secreted ATP and high-mobility group box 1 protein, which recruit and activate antigen-presenting cells to prime tumour-specific T lymphocytes. Underpinning these events are endoplasmic reticulum stress, autophagy, reactive oxygen species generation and finely tuned regulated cell death modalities. A diverse array of chemotherapeutic agents, radiotherapy, photodynamic therapies and novel nanomedicines have been shown to induce ICD. Integrating ICD induction with immune checkpoint blockade and modulation of the tumour microenvironment offers a promising route to overcome immune evasion, establish durable antitumour immunity and improve outcomes across multiple cancer types.

Research from Nature Portfolio

Recent studies have demonstrated the potential of targeted nanoparticles and molecular inhibitors to coordinate ICD induction with modulation of immunosuppressive cells. One approach employed hyaluronic acid–bilirubin nanoparticles to deliver a gp130 inhibitor selectively to tumour cells and tumour-associated myeloid cells, inducing ICD while re-programming macrophages towards a pro-inflammatory phenotype and enhancing response to anti-PD-L1 therapy. In another strategy, gadolinium-hemin nanoscale coordination polymers were shown to amplify radiation-induced oxidative stress, boosting DAMP release and synergising with checkpoint blockade to control primary and metastatic lesions. Foundational work has also revealed that high-dose crizotinib in combination with cisplatin can convert non-small cell lung cancer cells into active ICD vaccines, sensitising tumours to subsequent PD-1-directed immunotherapy.

Immunogenic Cell Death Mechanisms in Cancer Therapy publication trend

The graph below shows the total number of articles in immunogenic cell death mechanisms in cancer therapy across all publications each year (not limited to Nature Index journals).

Technical terms

Immunogenic cell death (ICD): A form of regulated tumour cell death that elicits adaptive antitumour immunity via emission of immunostimulatory signals.

Damage-associated molecular patterns (DAMPs): Endogenous molecules released or exposed by dying cells to activate and recruit immune cells.

Tumour-associated myeloid cells (TAMCs): Myeloid lineage cells within the tumour microenvironment that can suppress or promote immune responses.

Immune checkpoint blockade (ICB): Therapeutic antibodies that release inhibitory brakes on T cells, enhancing antitumour activity.

Endoplasmic reticulum stress (ER stress): A cellular condition triggering unfolded protein responses, often linked to DAMP exposure during ICD.

References

1. Hyaluronic acid-bilirubin nanomedicine-based combination chemoimmunotherapy. Nature Communications (2023).
2. Nanoscale coordination polymers induce immunogenic cell death by amplifying radiation therapy mediated oxidative stress. Nature Communications (2021).
3. Crizotinib-induced immunogenic cell death in non-small cell lung cancer. Nature Communications (2019).
4. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. Journal for ImmunoTherapy of Cancer (2020).
5. Immunogenic cell death induced by a new photodynamic therapy based on photosens and photodithazine. Journal for ImmunoTherapy of Cancer (2019).