Type I Interferon Signaling in Cancer Immunotherapy

Type I interferons (IFN-I) are pleiotropic cytokines that orchestrate both direct antitumour effects and the mobilisation of innate and adaptive immunity. Upon binding to the interferon-α/β receptor (IFNAR), IFN-I activate the JAK-STAT pathway, inducing hundreds of interferon-stimulated genes that inhibit tumour proliferation, enhance antigen presentation and promote cytotoxic effector functions. In the tumour microenvironment, IFN-I support dendritic cell maturation, NK cell activation and CD8+ T cell cross-priming, while counteracting regulatory cell populations. Clinical implementation as monotherapy has been limited by systemic toxicity and adaptive resistance mechanisms, including upregulation of immunosuppressive mediators and chronic signalling feedback loops. Contemporary strategies seek targeted delivery of IFN-I to tumours, rational combination with checkpoint inhibitors and exploitation of biomarkers to predict response. Harnessing the plasticity of IFN-I responses promises to augment current immunotherapies and overcome resistance across diverse cancer types.

Research from Nature Portfolio

Recent studies have devised innovative approaches to refine IFN-I delivery and exploit downstream signalling. One study engineered an anti-PD-L1 antibody fused to IFNα, which selectively activated IFNAR on host antigen-presenting cells without engaging tumour-intrinsic pathways. This dual-function molecule restored dendritic cell antigen presentation, overcame negative feedback from PD-L1 upregulation and reactivated cytotoxic T cells in resistant models, yielding durable tumour control. In a complementary investigation, the interplay between the transcription factor TP63 and STAT1 was shown to dictate interferon-regulated gene expression in squamous carcinoma. Although centring on interferon-γ, this work illuminated STAT1 chromatin occupancy and mutual repression mechanisms that are broadly relevant to type I interferon signalling, suggesting that tuning STAT1 activity may potentiate IFN-I–based immunotherapies.

Type I Interferon Signaling in Cancer Immunotherapy publication trend

The graph below shows the total number of articles in type i interferon signaling in cancer immunotherapy across all publications each year (not limited to Nature Index journals).

Technical terms

Type I interferons (IFN-I): A family of cytokines, including IFN-α and IFN-β, that bind the IFNAR receptor to initiate antiviral and antitumour gene programmes.

IFNAR: A heterodimeric cell-surface receptor that, upon ligand binding, activates JAK kinases and downstream STAT transcription factors.

JAK-STAT signalling: A pathway in which Janus kinases phosphorylate signal transducer and activator of transcription (STAT) proteins, driving expression of interferon-stimulated genes.

Antigen-presenting cell (APC): Immune cells, such as dendritic cells, that process and display antigenic peptides to T lymphocytes, initiating adaptive responses.

Checkpoint blockade: Therapeutic inhibition of immune checkpoints (for example PD-1/PD-L1) to restore T cell–mediated tumour eradication.

Tumour microenvironment (TME): The complex milieu of stromal, vascular and immune cells surrounding a tumour, which profoundly influences therapeutic efficacy.

References

1. Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance. Nature Communications (2018).
2. Reciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer. Nature Communications (2024).
3. A bispecific Clec9A-PD-L1 targeted type I interferon profoundly reshapes the tumor microenvironment towards an antitumor state. Molecular Cancer (2023).
4. Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment. Cancer Cell (2023).