Interleukin-12 in Cancer Immunotherapy

Interleukin-12 (IL-12) is a heterodimeric cytokine that orchestrates innate and adaptive immune responses against malignancies. By driving T helper 1 differentiation and stimulating natural killer and cytotoxic CD8+ T cells, IL-12 promotes the production of interferon-γ and enhances antigen presentation. Early clinical trials of systemic IL-12 revealed substantial antitumour activity but were limited by dose-dependent toxicity. Recent efforts have therefore focused on strategies to localise or regulate IL-12 delivery, mitigate adverse effects and synergise with other immunotherapies. Advances include engineering fusion proteins for targeted cis-delivery, employing pH-responsive nanocarriers to confine activity to acidic tumour niches, and combining IL-12 with immune checkpoint blockade or epigenetic modulators to convert “cold” tumours into immunologically inflamed lesions. Together, these developments revitalise IL-12 as a cornerstone of cytokine-based immunotherapy, offering renewed prospects for durable antitumour responses.

Research from Nature Portfolio

Recent studies have refined approaches to harness IL-12 in vivo while minimising systemic exposure. One investigation demonstrated that oral administration of a TLR7/8 agonist primes plasmacytoid dendritic cells via type I interferon, enabling topical application to induce c-Jun-dependent IL-12 release, inhibit angiogenesis and drive CD8+ T cell-mediated regression of both primary and metastatic lesions, especially when combined with PD-1 blockade. In parallel, an engineered fusion of a low-affinity IL-12 mutant to an anti-PD-1 antibody achieved preferential cis-activation of PD-1+ CD8+ tumour-infiltrating lymphocytes, eliciting potent systemic antitumour immunity with minimal toxicity and pronounced abscopal effects. Foundational work further revealed that targeted delivery of an IL-12 immunocytokine alongside a histone deacetylase inhibitor reprogrammes the tumour microenvironment towards a broadly inflamed state, yielding complete eradication in preclinical models and a biomarker signature predictive of favourable outcomes in multiple human cancers.

Interleukin-12 in Cancer Immunotherapy publication trend

The graph below shows the total number of articles in interleukin-12 in cancer immunotherapy across all publications each year (not limited to Nature Index journals).

Technical terms

Interleukin-12 (IL-12): A cytokine composed of two subunits that promotes Th1 responses and activates NK and CD8+ T cells.

Dendritic cell: A professional antigen-presenting cell that initiates and shapes adaptive immune responses.

Immune checkpoint blockade: Therapeutic inhibition of regulatory pathways such as PD-1/PD-L1 to restore T cell function.

Tumour microenvironment: The local cellular and molecular milieu surrounding a tumour, including immune, stromal and vascular components.

Abscopal effect: Regression of untreated metastatic lesions following localised therapy at a separate site.

Nanocytokine: A nanoscale carrier system that delivers cytokines selectively to target tissues based on environmental triggers.

References

1. Systemic IFN-I combined with topical TLR7/8 agonists promotes distant tumor suppression by c-Jun-dependent IL-12 expression in dendritic cells. Nature Cancer (2025).
2. Anti-PD-1 cis-delivery of low-affinity IL-12 activates intratumoral CD8+T cells for systemic antitumor responses. Nature Communications (2024).
3. Tumour-targeted interleukin-12 and entinostat combination therapy improves cancer survival by reprogramming the tumour immune cell landscape. Nature Communications (2021).
4. An IL‐12‐Based Nanocytokine Safely Potentiates Anticancer Immunity through Spatiotemporal Control of Inflammation to Eradicate Advanced Cold Tumors. Advanced Science (2023).
5. Engineered IL-7 synergizes with IL-12 immunotherapy to prevent T cell exhaustion and promote memory without exacerbating toxicity. Science Advances (2023).
6. Localized Interleukin-12 for Cancer Immunotherapy. Frontiers in Immunology (2020).