Inflammation Emerges as a Key Prevention Target

Lung cancer remains the leading cause of cancer-related deaths worldwide, with smoking representing the most significant risk factor. However, the disease also develops in some people without a history of smoking, highlighting the need for additional prevention strategies.

The MIT team focused on inflammatory processes that may contribute to early tumor development. Their work builds on earlier clinical observations from the CANTOS trial, which unexpectedly found that patients receiving an anti-inflammatory therapy targeting interleukin-1 beta (IL-1β) experienced lower rates of lung cancer. Although later studies showed limited benefit in patients with established disease, researchers have continued investigating whether inflammation could be interrupted before tumors fully develop.

Tracking Protease Activity in Early Cancer Development

To identify molecular drivers of inflammation-related tumor formation, investigators used specialized nanosensors previously developed in the laboratory of senior author Sangeeta Bhatia, PhD. These sensors are designed to detect proteases, enzymes that cut proteins and can influence both inflammation and cancer progression.

Using a genetically engineered mouse model predisposed to lung cancer, the researchers monitored protease activity during the earliest stages of disease development. Their analysis revealed a striking increase in caspase-1 activity in untreated mice that went on to develop lung tumors.

In contrast, mice treated with an IL-1β-blocking antibody showed significantly lower caspase-1 activity and developed fewer tumors. Importantly, elevated caspase-1 activity was concentrated within tumor tissue rather than surrounding healthy lung tissue.

Human Samples Support Preclinical Findings

To explore the relevance of these findings in humans, the team collaborated with investigators at Mass General Brigham and Harvard Medical School. Analysis of lung fluid samples demonstrated that patients with lung cancer had higher levels of caspase-1 activity than healthy individuals, despite having similar smoking histories.

These results suggest that caspase-1 may serve as both a biological marker of cancer-associated inflammation and a potential therapeutic target.

Repurposing an Existing Drug

The researchers next examined whether directly inhibiting caspase-1 could prevent tumor growth. Mice received either a caspase-1 inhibitor, an IL-1β antibody, or a combination of both treatments before tumors emerged.

The results were encouraging. Animals treated with either therapy alone developed fewer and smaller tumors than untreated controls. The combination approach produced the strongest effect, with nearly one in five mice remaining tumor-free throughout the study period.

One advantage of targeting caspase-1 is that inhibitors of the enzyme have already undergone human safety testing in clinical trials for conditions such as rheumatoid arthritis. Unlike antibody therapies that require intravenous administration, caspase-1 inhibitors can be taken orally, making them potentially more practical for long-term preventive use.

Toward the Concept of “Cancer Interception”

The findings support a growing field known as cancer interception, which aims to halt disease progression before cancer becomes clinically apparent. Researchers envision a future in which high-risk individuals could be identified through biomarker-based screening and offered preventive therapies tailored to their risk profile.

The MIT team hopes to advance caspase-1 inhibitors into clinical trials for lung cancer prevention and explore whether biomarkers associated with inflammatory pathways can help identify patients most likely to benefit.

While additional studies are needed to confirm efficacy in humans, the research provides compelling evidence that targeting inflammation, particularly through caspase-1 inhibition, may represent a promising strategy for reducing lung cancer incidence in vulnerable populations.