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Updated: Aug 16, 2026
Visualization of Inflammatory Caspases Induced Proximity in Human Monocyte-Derived Macrophages
Published on: April 6, 2022
Multimodal profiling of pro-inflammatory protease activity identifies caspase-1 as a target for lung cancer
Cathy S Wang1,2, Qian Zhong2,3, Shih-Ting Wang2
1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract:
Systemic inhibition of interleukin-1b (IL-1b) has been shown to reduce the incidence of lung cancer in patients in years after treatment, but knowledge gaps surrounding its activation and role in the tumor microenvironment hinder cancer interception. We developed activity-based technologies to probe inflammation in early lung cancer and identified a translational target candidate. Probes sensitive to IL-1b-activating proteases were designed and applied to a murine model of inflammatory lung cancer, Kras/Trp53-mutant mice with SIINFEKL expression (KPS). Our nanosensors revealed elevated caspase-1 expression and activity in tumors, highlighting the importance of caspase-1 processing IL-1b during cancer development. We conducted a preclinical combination therapy trial by administering IL-1b blockade and caspase-1 inhibition. We observed significant reduction in lung cancer, including complete ablation of tumor incidence in nearly 20% of KPS mice. Our approach to understanding the interplay of protease activity and cytokine activation supports new strategies to mitigate inflammation and intercept lung cancer progression.
Insights
Targeting interleukin-1b (IL-1b) and caspase-1 in lung cancer shows promise. Combination therapy significantly reduced lung cancer incidence in a preclinical model, offering new interception strategies.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Interleukin-1b (IL-1b) systemic inhibition may reduce lung cancer incidence, but its activation and role in the tumor microenvironment require further investigation.
- Knowledge gaps hinder effective lung cancer interception strategies.
- Inflammation plays a critical role in lung cancer development and progression.
Purpose of the Study:
- To develop activity-based technologies for probing inflammation in early lung cancer.
- To identify and validate translational target candidates for cancer interception.
- To investigate the role of caspase-1 in processing IL-1b during lung cancer development.
Main Methods:
- Development of activity-based probes sensitive to IL-1b-activating proteases.
- Application of nanosensors to a Kras/Trp53-mutant murine model of inflammatory lung cancer (KPS mice).
- Preclinical combination therapy trial involving IL-1b blockade and caspase-1 inhibition.
Main Results:
- Nanosensors revealed elevated caspase-1 expression and activity in lung tumors.
- Combination therapy significantly reduced lung cancer incidence in KPS mice.
- Complete ablation of tumor incidence was observed in nearly 20% of treated KPS mice.
Conclusions:
- Caspase-1 processing of IL-1b is crucial during lung cancer development.
- Targeting the interplay of protease activity and cytokine activation offers a novel strategy for lung cancer interception.
- This approach holds potential for mitigating inflammation and intercepting lung cancer progression.
