Updated project metadata. Tumor cells can induce their own advantageous microenvironment. Here, we describe aberrant cathepsin S (CTSS) activity to modulate T-cell activation in follicular lymphoma (FL). In donor-derived FLs following bone marrow transplantation, we identified independent acquisition of CTSS mutations at Y132 in the donor´s and recipient's tumors. In a larger cohort, 6% of FL (20/312) harbored CTSS mutations, mostly Y132D, another 14% had CTSS amplification (40/280). Y132D leads to accelerated conversion from pro-CTSS to active CTSS and increased substrate cleavage, including CD74, which regulates MHC-II restricted antigen-presentation. In co-culture experiments, CTSS mutant lymphoma cells induced increased antigen-specific CD4+ T-cell activation. Moreover, antigen-processing was the top upregulated pathway in CTSS mutant primary FL biopsies. Thus, aberrant CTSS activity is a promising target in lymphoma.