Abstract
Proteases play a crucial role in cancer progression and are traditionally known for their protumorigenic role by degrading the extracellular matrix (ECM). Emerging evidence indicates that proteases, such as caspases, cathepsins, and ubiquitin-specific proteases (USPs), regulate diverse immunomodulatory substrates or signals in the tumor microenvironment (TME), generating symbiotic interactions between cancer cells and immune cells. These interactions are critical for tumor progression and immunotherapy resistance across cancer types. In this review, we highlight recent insights into protease-mediated tumor-immune cell crosstalk, emphasizing how this symbiosis affects tumor progression and immunosuppression. Moreover, we discuss therapeutic strategies that exploit protease-mediated tumor-immune cell interactions to inhibit tumor progression and sensitize immunologically 'cold' tumors to immunotherapies, especially immune checkpoint inhibitor (ICI) therapy.