Multimodal profiling of pro-inflammatory protease activity identifies caspase-1 as a target for lung cancer interception.

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.