Cysteine peptidases emerge as key regulators of antitumor immunity and promising therapeutic targets

Antigen-presenting cells serve as the central bridge between innate and adaptive immunity, with dendritic cells and tumor-associated macrophages playing indispensable roles in initiating CD8⁺ T cell-mediated antitumor responses. However, within the immunosuppressive tumor microenvironment, these cells often become functionally impaired or tolerized, constituting one of the core mechanisms of tumor immune evasion. A comprehensive review published on July 17, 2026, in iMetaMed provides the first systematic framework elucidating how cysteine peptidases, particularly cathepsins B, S, L, and X, govern antigen-presenting cell function and antitumor immunity.

The research team, led by scientists from Shanghai Jiao Tong University School of Medicine, Shanghai Cancer Institute, Inner Mongolia Medical University, and Selcuk University in Turkey, synthesized recent advances in understanding the molecular mechanisms by which cysteine peptidases regulate antigen processing, MHC molecule loading, cross-presentation, and immune regulatory signaling pathways. The review establishes that these enzymes act as molecular scissors within the lysosomal compartments of antigen-presenting cells, with their activity directly determining the efficiency, diversity, and ultimate immunogenicity of antigenic peptide generation.

A central discovery of the review is the identification of two core pathways through which cysteine peptidases drive tumor immune evasion. The first pathway involves excessive antigen degradation within tumor-associated macrophages, where abnormally elevated cathepsin activity leads to the over-degradation of phagocytosed tumor antigens, destroying key immunogenic epitopes before they can bind to MHC molecules. The second pathway centers on PD-L1 regulation, where cathepsin S modulates PD-L1 expression on tumor cells and macrophages, directly suppressing T cell activity through the PD-1/PD-L1 axis. The review also reveals that cysteine peptidases exert dose-dependent dual regulation of Toll-like receptor signaling pathways, with moderate activity promoting immune activation while excessive activity causes premature signal attenuation.

The authors systematically compared cysteine peptidase expression and functional patterns across multiple cancer types, revealing striking cancer-type specificity. In colorectal cancer, cathepsin S is consistently upregulated in tumor-associated macrophages and correlates positively with PD-L1 expression and poor response to anti-PD-1 therapy. In melanoma, single-cell proteomics has identified elevated cathepsin L and B activity in a subset of tumor-educated dendritic cells associated with Treg induction and immune tolerance. In pancreatic ductal adenocarcinoma, cathepsins B and L are overexpressed in cancer-associated fibroblasts and tumor cells promoting metastasis, whereas cathepsin S activity remains relatively low, suggesting distinct immune evasion mechanisms. These findings underscore that therapeutic targeting of cysteine peptidases must be cancer-type-specific and patient-stratified based on enzymatic activity profiling rather than transcript levels alone.

The review comprehensively evaluates therapeutic strategies targeting cysteine peptidases, including small-molecule inhibitors such as the broad-spectrum inhibitor E64 and the selective cathepsin S inhibitor LHVS. Intelligent nanocarriers like Ft-E64/Hf@Lipo have been designed to co-deliver cysteine protease inhibitors and radiosensitizers, remodeling the antigen-presenting function of tumor-associated macrophages. Preclinical models demonstrate that combining cathepsin B inhibition with PD-1 antibodies markedly increases T cell tumor infiltration and cytotoxic capacity, producing strong synergistic antitumor effects in melanoma, lung cancer, and colorectal cancer models. For immunologically cold tumors, this combination therapy can convert them to hot tumors by enhancing T cell infiltration and activation, improving response rates to immune checkpoint blockade.

The review also confronts critical challenges facing the field, including compensatory resistance mechanisms where prolonged exposure to broad-spectrum inhibitors leads to upregulation of alternative cathepsins through TFEB-mediated lysosomal stress responses. The authors emphasize that overcoming translational bottlenecks in spatiotemporal dynamics, delivery specificity, and patient stratification requires integrated multi-omics, gene-editing, and AI-driven approaches for precision immunotherapy. By addressing these challenges, cysteine peptidase-targeted therapies hold immense potential to revolutionize cancer immunotherapy, improving response rates and patient outcomes by reactivating robust antitumor immune responses.