The multifaceted roles of cathepsins in immune and inflammatory responses: implications for cancer therapy, autoimmune diseases, and infectious diseases

Abstract

The cathepsin family comprises lysosomal proteases that play essential roles in various physiological processes, including protein degradation, antigen presentation, apoptosis, and tissue remodeling. Dysregulation of cathepsin activity has been linked to a variety of pathological conditions, such as cancer, autoimmune diseases, and neurodegenerative disorders. Understanding the functions of cathepsins is crucial for gaining insights into their roles in both health and disease, as well as for developing targeted therapeutic approaches. Emerging research underscores the significant involvement of cathepsins in immune cells, particularly T cells, macrophages, dendritic cells, and neutrophils, as well as their contribution to immune-related diseases. In this review, we systematically examine the impact of cathepsins on the immune system and their mechanistic roles in cancer, infectious diseases, autoimmune and neurodegenerative disorders, with the goal of identifying novel therapeutic strategies for these conditions.

Keywords: Autoimmune diseases; Cancer therapy; Cathepsins in immune cells; Infectious diseases.

Fig. 1

Cathepsins in the processing and maturation of MHC II molecules. During the maturation of MHC II molecules, the invariant chain is progressively degraded, leaving behind a peptide segment known as CLIP. CLIP acts as a “placeholder” within the antigen-binding groove of the MHC II molecule, preventing the binding of non-specific peptides until the MHC II molecule can bind to the appropriate antigenic peptide. This process occurs in the cell’s endoplasmic reticulum and endosomes and involves the fusion of endosomes with lysosomes, where lysosomal cathepsins play a role in degrading the invariant chain

Fig. 2

The regulatory role of cathepsins in immune cells influences disease progression. Naive CD4 + T cells, when activated through TCR engagement and co-stimulation, differentiate into Th1, Th2, Th17, and Treg cells, each producing a distinct set of cytokines. Th1 cells produce IFNγ and TNFα, which drive macrophages to differentiate into the M1 phenotype, whereas Th2 cells secrete IL-4, IL-5, IL-9, and IL-13, promoting the M2 macrophage phenotype. Cathepsins modulate this differentiation process; their inhibition can shift M2 macrophages to the M1 phenotype, potentially curbing cancer progression. Th17 cells synthesize IL-17, IL-21, and IL-22, which induce the formation of NETs, a process regulated by cathepsins and associated with tumor metastasis promotion. Treg cells produce IL-10 and TGF-β, but their suppressive function can be compromised by the cleavage of the surface molecule CD25 by CTSW

Fig. 3

Mechanisms by which cathepsins exert their effects in various diseases through multiple molecular patterns. (A) Cathepsin X-induced lysosomal leakage results in the cleavage of the C-terminal domain of neuron-specific enolase (NSE), causing its dysfunction and leading to neuroinflammation and neurodegeneration. This process also enhances the production of reactive oxygen species (ROS), causing oxidative stress and inflammatory responses, which create a positive feedback loop with lysosomal membrane permeabilization (LMP). (B) Activation of Toll-like receptors (TLRs) leads to the activation of the transcription factor NF-κB, which promotes the formation of the NLRP3 inflammasome. This facilitates the transcription and translation of pro-inflammatory cytokine precursors such as pro-IL-1β and mediates pyroptosis through GSDMD. (C) The cleavage of the S2 subunit of the SARS-CoV-2 spike protein is a critical step for viral entry into host cells, occurring primarily at the S1/S2 cleavage site and mediated mainly by cathepsin L