Cytokine-Based Immunotherapy in Cancer Treatment

Cytokine-based immunotherapy leverages the potent regulatory functions of soluble immune mediators to orchestrate antitumour immune responses. Early clinical success with high-dose interleukin-2 and interferon-α demonstrated that exogenous cytokines can induce durable remissions in subsets of melanoma and renal cell carcinoma patients. However, systemic administration of native cytokines is limited by rapid clearance, dose-limiting toxicities and unwanted expansion of regulatory cells. To overcome these challenges, modern strategies engineer cytokines for enhanced half-life, receptor selectivity and tumour targeting. These include antibody–cytokine fusion proteins that localise activity within the tumour microenvironment, receptor-biased agonists that preferentially activate effector over suppressive lymphocytes, and protease-activated prodrugs that unmask cytokine function in situ. Such innovations allow for potent local stimulation of natural killer cells and cytotoxic T lymphocytes while minimising off-target effects. Combining cytokines with immune checkpoint inhibitors, radiation or adoptive cell therapies has further amplified efficacy by reshaping the tumour milieu towards a Th1-polarised, inflammatory state. Collectively, cytokine-based approaches are redefining the therapeutic landscape by offering modular platforms capable of precise immune modulation across a broad range of solid and haematological malignancies.

Research from Nature Portfolio

Recent studies have shown that intratumoral delivery of CD45-anchored interleukin-12 followed by interleukin-15 triggers systemic antitumour immunity, eradicating both treated and distant lesions without toxicity. This approach sustains cis and trans signalling in tumour-draining lymph nodes to reprogramme CD8+ T cells with an antiviral transcriptional signature. Complementing this, a novel immunocytokine that docks cis-wise to PD-1 and engages IL-2Rβγ has been developed to expand ‘better effector’ stem-like CD8+ T cells in the absence of IL-2Rα binding. This PD-1-cis IL-2R agonist differentiates a superior effector population, resists terminal exhaustion and enhances checkpoint blockade efficacy in preclinical cancer models.

Cytokine-Based Immunotherapy in Cancer Treatment publication trend

The graph below shows the total number of articles in cytokine-based immunotherapy in cancer treatment across all publications each year (not limited to Nature Index journals).

Technical terms

Cytokine: A small secreted protein that mediates cell-to-cell communication in the immune system, dictating cell proliferation, differentiation and activation.

Immunocytokine: A fusion protein combining a cytokine with a tumour-targeting antibody moiety to concentrate immune stimulation within the tumour microenvironment.

PD-1 cis-targeting: A strategy in which a cytokine agonist is engineered to bind PD-1 on the same T cell, ensuring co-engagement of the cytokine receptor in a single immune synapse.

Tumour microenvironment (TME): The complex milieu surrounding tumour cells, including immune cells, stromal components and soluble factors that collectively influence tumour progression and therapy response.

Protease-activated prodrug: A masked cytokine construct that is enzymatically cleaved by tumour-associated proteases to release the active cytokine preferentially within tumours.

References

1. Targeting cytokine and chemokine signaling pathways for cancer therapy. Signal Transduction and Targeted Therapy (2024).
2. Simultaneous targeting of PD-1 and IL-2Rβγ with radiation therapy inhibits pancreatic cancer growth and metastasis. Cancer Cell (2023).
3. Local delivery of cell surface-targeted immunocytokines programs systemic antitumor immunity. Nature Immunology (2024).
4. PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells. Nature (2022).
5. A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy. Nature Communications (2021).