Lung metastases are the second most common manifestation in oncology, occurring in about 30% of cases. According to Swiss clinicians, the median survival of patients with lung metastases is about 10 months, and the 5-year survival rate is below 5%.
Type I interferons (IFN-I) activate anti-tumor immunity by recruiting T-cells to tumors for clearance. However, tumors suppress endogenous IFN-I production, leaving T-cells exhausted and dysfunctional. This immune shield facilitates metastasis. Recognizing the critical role of IFN-I, researchers developed interferon-based drugs.
The first approved generation of drugs was human IFN-I. Due to its short half-life, IFN-I required high doses and frequent injections. Side effects include liver toxicity and inflammation-induced cytokine storm. The second generation required fewer injections because of its longer half-life. However, toxicity remained. Both generations of injectable interferon drugs affected the entire body but were unable to target tumor cells.
Lipid Nanoparticles With IFN-I mRNA Suppress Lung Metastases
U.S. researchers developed lipid nanoparticles containing type I interferon mRNA. These particles reprogram tumor cells to produce their own IFN-I, avoiding the side effects of earlier generations.
Due to lipid properties, nanoparticles were preferentially taken up by tumor cells. Inside the cells, they stimulated IFN-I production. In mouse models, treatment markedly reduced lung metastases.
Key findings:
- No cytokine storm.
- No elevation of liver enzyme markers.
- No need for repeated injections – tumor cells produced IFN-I themselves.
The nanoparticle is a promising candidate for third-generation IFN-based lung metastasis immunotherapy.
Study Design
First, the team engineered a lipid nanoparticle carrying type I interferon mRNA. A related particle had previously been used to deliver genetic cargo into tumor cells in cancer patients.
A key feature of the new particle was its preferential uptake by rapidly dividing cancer cells, which was expected to lower toxicity to healthy, slowly dividing cells.
Next, the efficacy of a single injection was tested in mice. Primary tumors were established by injecting cancer cells, and spontaneous lung metastases were modeled by tail-vein injection of tumor cells. The cancer cell lines used mirrored common human cancers: breast carcinoma, colorectal carcinoma, and melanoma.
In the final experiments, the team simulated human therapy. Human IFN-I mRNA was packaged into the lipid nanoparticle, and humanized mice (given human blood) were used. Human tumor cells were introduced to form a primary tumor and lung metastases, after which mice were treated with the nanoparticle.
Clinical Outcomes in Mouse Models
Treatment with the lipid nanoparticle carrying IFN-I mRNA not only effectively suppressed lung metastases but also reduced the primary tumor size and increased mouse survival. Efficacy was demonstrated both in conventional and in humanized mice.
These results are clearly visible in the graphs, where red denotes mice that received the IFN-I mRNA nanoparticle and blue denotes those that received an empty lipid nanoparticle.
The most striking findings concern lung metastases. In 100% of mice receiving the empty particle, lung metastases developed, whereas in the treatment group, only 20% did (left graph). The number of metastatic nodules in treated mice was also dramatically lower (right graph).
Image source: https://pmc.ncbi.nlm.nih.gov/articles/PMC12314986/
Treatment also significantly curbed primary tumor growth – both size (left graph) and weight (right graph) decreased – though these differences did not reach statistical significance:
Image source: https://pmc.ncbi.nlm.nih.gov/articles/PMC12314986/
The clinical impact appeared as improved survival in mice treated with the IFN-I mRNA nanoparticle (green curve) compared with mice given the empty particle (red curve):
Image source: https://pmc.ncbi.nlm.nih.gov/articles/PMC12314986/
Biochemical Results
In treated mice, anti-tumor immunity was activated.
The interferon mRNA inside the nanoparticles successfully stimulated endogenous interferon production. IFN-I levels rose substantially in serum (top graph). IFN production also increased in cells of the primary tumor (bottom left) and in lung metastasis cells (bottom right). In all three plots, the left bars represent mice given the empty particle:
Image source: https://pmc.ncbi.nlm.nih.gov/articles/PMC12314986/
In humanized mice, nanoparticles carrying human IFN-I mRNA led tumor cells to produce human IFN-I.
Endogenous IFN-I then triggered downstream anti-tumor immune programs. The team measured interferon-regulated chemokines that recruit T cells to tumors – Cxcl9 and Cxcl10. In the graphs below, green denotes treated mice and red indicates controls.
Image source: https://pmc.ncbi.nlm.nih.gov/articles/PMC12314986/
Finally, the numbers of tumor-infiltrating T cells in the lungs were quantified – CD4+ and CD8+ populations increased in treated animals (green) versus controls (red):
Image source: https://pmc.ncbi.nlm.nih.gov/articles/PMC12314986/
From these data, the authors conclude that the IFN-I mRNA lipid nanoparticle activated anti-tumor immunity within tumor cells, suppressing lung metastases, shrinking primary tumors, and extending survival.
Importantly, one injection sufficed to activate anti-tumor immunity – an advantage over first- and second-generation interferon drugs that require multiple injections to achieve a therapeutic effect.
Safety Profile
Earlier interferon drugs were limited by two significant adverse effects:
- Excessive inflammatory responses and cytokine storm;
- Liver toxicity.
The researchers compared pro-inflammatory cytokine levels between treated and control mice. Levels were comparable in both groups, except IL-23, which was significantly lower in the treatment group. The figure shows seven pro-inflammatory cytokines (green = treated, red = empty particle):
Image source: https://pmc.ncbi.nlm.nih.gov/articles/PMC12314986/
Next, they assessed liver enzymes – alanine aminotransferase (ALT) and alkaline phosphatase (ALP) – key indicators of hepatotoxicity. The graphs show no significant changes in ALP or ALT after treatment, supporting precise targeting of the nanoparticle to tumor cells rather than healthy tissues:
Image source: https://pmc.ncbi.nlm.nih.gov/articles/PMC12314986/
These findings support the notion that the lipid nanoparticle carrying type I interferon mRNA is a potentially safe and effective third-generation interferon-based drug for cancer immunotherapy in patients with lung metastases.
Conclusions
To prevent lung metastases, researchers created a lipid nanoparticle containing type I interferon mRNA. A single injection reduced lung metastases fivefold. The treatment also reduced primary tumor size and improved survival.
Biochemical analyses showed that the particle stimulated endogenous IFN-I production in tumor cells, which in turn induced chemokines that recruited T cells to the tumor.
The nanoparticle avoids the hallmark side effects of prior interferon-based immunotherapies – it does not cause liver toxicity or cytokine storm – thanks to its preferential uptake by rapidly dividing cancer cells.
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References
- Lipid nanoparticle-delivered IFNα2 activates Cxcl9 to increase T cell tumor recruitment to suppress lung metastasis
- Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment
- Risk factors for survival after lung metastasectomy in colorectal cancer patients: systematic review and meta-analysis
- Next generation of tumor-activating type I IFN enhances anti-tumor immune responses to overcome therapy resistance
