Cysteine Peptidases in Antitumor Immunity: Unraveling Antigen‐Presenting Cell Regulation and Therapeutic Potential

Abstract

This review systematically summarizes the central role of cysteine peptidases in modulating antigen‐presenting cell (APC) function and antitumor immune responses, highlighting their critical significance in overcoming tumor immune evasion. Current research has established that cysteine peptidase subtypes, including cathepsins B, S, L, and X, exert multifaceted effects on antigen processing, MHC molecule loading, cross‐presentation, and immune regulatory signaling pathways in dendritic cells and tumor‐associated macrophages. Dysregulation of these enzymes contributes to impaired antigen presentation, T cell dysfunction, and immunosuppressive tumor microenvironment formation, representing a major barrier to effective immunotherapy. Despite significant progress in elucidating their molecular mechanisms, gaps remain in understanding cell‐type specificity, spatiotemporal dynamics, and context‐dependent functions. This review integrates recent advances in peptidase‐targeted strategies, including small‐molecule modulators, nanocarriers, and combination therapies with immune checkpoint inhibitors, providing a comprehensive framework for translating basic research into clinical applications and addressing the urgent need for novel immunotherapeutic targets.