Lung cancer remains one of the leading causes of cancer-related deaths, with smoking being the major risk factor. However, lung cancer also develops in people who have never smoked, highlighting the need for new approaches that could identify and prevent the disease before tumors become established. Now, researchers at the Massachusetts Institute of Technology (MIT) have identified an inflammatory enzyme that could become a potential target for preventing lung cancer in people at elevated risk.
The new study, published in Science Advances, suggests that blocking caspase-1, an enzyme involved in inflammation, can significantly reduce the development and growth of lung tumors in mice. The researchers found that caspase-1 was highly active during early lung tumor development and that treating at-risk mice with a small-molecule caspase-1 inhibitor resulted in fewer and smaller tumors.
The findings raise the possibility of using an existing investigational drug as a preventive treatment for people who are considered to have a high risk of developing lung cancer. Unlike many biological medicines that require intravenous administration, caspase-1 inhibitors can be taken orally, potentially making them more convenient for long-term preventive use.
From inflammation to cancer prevention
The study builds on earlier evidence suggesting that chronic inflammation in the lungs can contribute to cancer development. One important clue came from the CANTOS clinical trial, which was originally designed to investigate whether reducing inflammation could lower the risk of cardiovascular events. Researchers unexpectedly observed that patients receiving an antibody targeting the inflammatory molecule IL-1 beta had lower rates of lung cancer in a subset of participants.
Although subsequent studies found that blocking IL-1 beta had little effect in people who already had established lung cancer, the findings raised an important question: could targeting the inflammatory pathway before a tumor develops help prevent lung cancer?
MIT researchers led by Sangeeta Bhatia investigated this possibility by looking upstream of IL-1 beta. The mature, active form of IL-1 beta requires cleavage by a protease, prompting the researchers to investigate whether one of these enzymes might play an important role in the inflammatory environment associated with early lung cancer.
Their attention focused on caspase-1, a protease known to participate in inflammatory processes.
A nanosensor helps identify the enzyme
Bhatia's laboratory has spent years developing nanosensors capable of detecting protease activity inside tissues. These sensors contain nanoparticles decorated with small peptide sequences that can be cut by specific proteases. When the targeted enzymes become active, the cleavage of these peptides produces a detectable signal.
For the new study, the researchers adapted this technology to identify proteases that become active during the early stages of lung cancer development.
The team used a genetically engineered mouse model known as KPS, developed by MIT researcher Tyler Jacks. The model carries cancer-associated mutations in the p53 and Kras genes and also expresses a peptide designed to stimulate T-cell activity and inflammation in the lungs.
Importantly, the researchers designed the experiments to study cancer risk before tumors became detectable, allowing them to investigate biological changes occurring during the earliest stages of tumor development.
Caspase-1 activity rises inside developing tumors
Five weeks after inducing cancer-associated mutations, some of the mice received an antibody designed to block IL-1 beta, while other animals remained untreated. Three weeks later, the researchers used their nanosensors to examine protease activity in the lungs.
The results revealed a striking difference. In untreated mice, which developed lung tumors, caspase-1 activity was strongly elevated. In contrast, mice treated with the IL-1 beta-blocking antibody had lower caspase-1 activity and developed fewer tumors.
The researchers also found that caspase-1 activity was concentrated primarily within the lung tumors rather than in nearby healthy lung tissue. This suggested that the enzyme may be particularly important in the tumor-associated inflammatory environment.
The findings were further supported by an analysis of a small number of human lung fluid samples conducted in collaboration with researchers at Harvard Medical School and Mass General Brigham. Patients with lung cancer showed higher caspase-1 activity than healthy donors, despite having a common smoking history.
Blocking caspase-1 reduces tumor development
The researchers then asked whether directly inhibiting caspase-1 could reproduce the protective effect seen with IL-1 beta inhibition.
Before tumors developed, at-risk mice were treated with either a caspase-1 inhibitor, an IL-1 beta antibody, or both treatments. The results were encouraging.
Mice receiving either treatment alone developed smaller and fewer tumors than untreated animals. The combination of the caspase-1 inhibitor and IL-1 beta antibody produced an even stronger effect, with nearly 20% of the mice never developing tumors at all.
These findings suggest that caspase-1 may represent an important point in the inflammatory pathway that contributes to lung tumor formation.
Why this could be important for cancer prevention
Cancer treatment generally begins after a tumor has already formed. Cancer prevention, however, takes a different approach: identifying individuals at elevated risk and intervening before cancer becomes established.
This concept is sometimes referred to as “cancer interception.”
Sangeeta Bhatia, senior author of the study, suggested that a future scenario could involve identifying people at particularly high risk of lung cancer and providing preventive medication before tumors develop.
Such an approach could be especially significant for lung cancer because smoking remains a major risk factor, while cases also occur among people who have never smoked. The researchers envision a future in which biomarkers could help identify individuals most likely to benefit from preventive treatment.
An important advantage: the drug has already been tested in humans
One of the most interesting aspects of the findings is that the caspase-1 inhibitor investigated by the MIT researchers is not an entirely new experimental compound.
According to the researchers, caspase-1 inhibitors have previously entered clinical trials for conditions including rheumatoid arthritis and other diseases. This means that the drug class has already undergone human safety evaluation, potentially creating an opportunity for drug repurposing.
If future research confirms the cancer-prevention potential, the existing human safety data could potentially help accelerate development compared with starting from a completely new drug molecule.
The oral availability of caspase-1 inhibitors could also be advantageous for preventive therapy, as long-term prevention would potentially be easier with an orally administered medicine than with an intravenous antibody.
The role of biomarkers could be crucial
Not everyone at risk of lung cancer would necessarily respond in the same way to an anti-inflammatory preventive treatment. Identifying the right individuals could therefore be critical.
The MIT researchers point to work from the Francis Crick Institute's Swanton laboratory, which identified a collection of proteins across different biological pathways and cell types that could potentially predict which patients would respond to IL-1 beta-targeting treatment.
Such biomarkers could eventually help researchers design clinical trials that enroll people most likely to benefit from inflammation-targeting strategies.
This could transform the concept from simply giving an anti-inflammatory drug to people at high risk into a more precise biomarker-guided cancer prevention strategy.
From mouse models to human prevention
Despite the encouraging findings, the study does not establish that caspase-1 inhibitors can prevent lung cancer in humans.
The strongest experimental evidence in this study comes from genetically engineered mice. The researchers also found increased caspase-1 activity in a small set of human lung fluid samples, but this human evidence is not sufficient to demonstrate that blocking the enzyme will prevent cancer.
A clinical trial will therefore be necessary to determine whether the approach is safe and effective as a lung cancer prevention strategy in people.
The researchers hope to eventually test the drug in a clinical trial, potentially using biomarkers to identify individuals who are most likely to respond.
A potential new direction in lung cancer prevention
The study highlights a growing interest in targeting the biological processes that occur before cancer becomes clinically detectable. Instead of waiting for a tumor to develop and then treating it, researchers are increasingly investigating whether inflammation, immune activity and other early biological changes can be intercepted.
Caspase-1 could become an important target in this emerging field. By interfering with an inflammatory pathway linked to IL-1 beta, researchers were able to substantially reduce lung tumor development in a mouse model.
The next major question is whether the same mechanism operates in people and whether an existing caspase-1 inhibitor can safely interrupt the process before lung cancer develops.
If future clinical studies confirm these findings, an already investigated class of anti-inflammatory drugs could potentially be repurposed for lung cancer prevention, offering a new strategy for people at particularly high risk of the disease.
