The Tumor Proteolytic Landscape: A Challenging Frontier in Cancer Diagnosis and Therapy

Abstract

In recent decades, dysregulation of proteases and atypical proteolysis have become increasingly recognized as important hallmarks of cancer, driving community-wide efforts to explore the proteolytic landscape of oncologic disease. With more than 100 proteases currently associated with different aspects of cancer development and progression, there is a clear impetus to harness their potential in the context of oncology. Advances in the protease field have yielded technologies enabling sensitive protease detection in various settings, paving the way towards diagnostic profiling of disease-related protease activity patterns. Methods including activity-based probes and substrates, antibodies, and various nanosystems that generate reporter signals, i.e., for PET or MRI, after interaction with the target protease have shown potential for clinical translation. Nevertheless, these technologies are costly, not easily multiplexed, and require advanced imaging technologies. While the current clinical applications of protease-responsive technologies in oncologic settings are still limited, emerging technologies and protease sensors are poised to enable comprehensive exploration of the tumor proteolytic landscape as a diagnostic and therapeutic frontier. This review aims to give an overview of the most relevant classes of proteases as indicators for tumor diagnosis, current approaches to detect and monitor their activity in vivo, and associated therapeutic applications.

Keywords: protease activity; protease diagnostic and therapeutic modalities; tumor microenvironment.

Figure 1

Knowledge of tumor proteolysis translates into diagnostic and therapeutic modalities. Proteases in the tumor microenvironment belong to different protease families and originate from tumor and other cells present in the tumor microenvironment. They exhibit different patterns of localization and activity that may overlap and generate an intricate proteolytic landscape with roles in mechanisms behind cancer hallmarks. Knowledge of the role of proteolysis in cancer can support diagnosis, staging, mechanistic studies, disease monitoring and therapy.

Figure 2

Protease-responsive nanodevices and applications of protease-responsiveness. Protease-responsiveness can be centrally integrated into various diagnostic modalities that utilize optical, MRI, PET, SPECT or CT imaging for detection of protease activity (left). Protease-responsiveness can also serve as a trigger for activation of prodrugs and antibody-drug conjugates or on-site targeting of cancer drugs via polymeric nanoparticles, liposomes and inorganic nanoparticles (right).