Taken together, we propose that CTSE plays a context-dependent role in the pathogenesis of PC: in the early stages, CTSE within cancer cells may limit invasion and migration by suppressing the PI3K-AKT pathway and EMT, and in later stages, CTSE expression by immune cells in the tumor microenvironment may increase total CTSE levels, thereby serving as a favorable prognostic indicator. Here, CTSE is linked to pachyonychia congenita.