Interferon-γ Mediated Immune Responses in Tumor Microenvironments

Interferon-γ (IFN-γ) is a central cytokine in cell-mediated immunity, exerting multifaceted effects within the tumour microenvironment (TME). Upon recognition of tumour antigens by natural killer cells or cytotoxic T lymphocytes, IFN-γ is secreted and binds to its receptor complex on a variety of cell types. This engagement activates the JAK/STAT signalling cascade, driving transcription of genes involved in antigen presentation, growth arrest and apoptosis. In addition to direct antiproliferative actions on cancer cells, IFN-γ modulates stromal and vascular compartments, reshaping the extracellular matrix and controlling local perfusion. Paradoxically, chronic or dysregulated IFN-γ signalling can induce immune checkpoints, such as PD-L1, and impair the maintenance of stem-like T cell populations, thus limiting long-term antitumour immunity. The balance between these pro- and antitumour functions is influenced by cytokine concentration, duration of exposure and the composition of the TME, with profound implications for immunotherapy design and patient stratification.

Research from Nature Portfolio

Recent studies have revealed that IFN-γ carries a cryptic extracellular-matrix-binding domain that sequesters the cytokine within the TME, preventing excessive systemic dissemination and toxicity. Removal of this domain leads to elevated circulating levels of IFN-γ, provoking weight loss and organ damage despite retained receptor binding and bioactivity. This local retention mechanism ensures potent antitumour activity without undue collateral injury during prolonged immune responses.

Further work has shown that IFN-γ signalling in intra-tumoral CD8+ T cells imposes a negative feedback loop on antitumour immunity. Continuous exposure to IFN-γ diminishes the pool of stem-like T cells by reducing their clonal diversity and proliferative capacity. The resulting contraction of intermediate-exhausted subsets correlates with poorer responses to checkpoint blockade, highlighting the need to modulate IFN-γ sensitivity in adoptive and checkpoint therapies to maintain durable tumour control.

Interferon-γ Mediated Immune Responses in Tumor Microenvironments publication trend

The graph below shows the total number of articles in interferon-γ mediated immune responses in tumor microenvironments across all publications each year (not limited to Nature Index journals).

Technical terms

Cytokine: A signalling protein secreted by immune cells that coordinates responses to infection or malignancy.

Tumour microenvironment (TME): The complex milieu of cancer cells, immune cells, stromal elements and signalling molecules surrounding a tumour.

JAK/STAT pathway: A cell-surface receptor‐initiated cascade involving Janus kinases and signal transducers and activators of transcription that regulates gene expression.

Extracellular matrix (ECM): A network of proteins and polysaccharides providing structural support and biochemical cues within tissues.

Stem-like T cells: A subset of T lymphocytes with self-renewal capacity and the potential to generate effector progeny for sustained antitumour responses.

References

1. ERK mediates interferon gamma-induced melanoma cell death. Molecular Cancer (2023).
2. IFNγ binding to extracellular matrix prevents fatal systemic toxicity. Nature Immunology (2023).
3. IFNγ signaling in cytotoxic T cells restricts anti-tumor responses by inhibiting the maintenance and diversity of intra-tumoral stem-like T cells. Nature Communications (2023).
4. Tumor growth suppression in adoptive T cell therapy via IFN-γ targeting of tumor vascular endothelial cells. Theranostics (2024).
5. Down-regulation of DNA key protein-FEN1 inhibits OSCC growth by affecting immunosuppressive phenotypes via IFN-γ/JAK/STAT-1. International Journal of Oral Science (2023).