Cathepsin S regulates germinal center reactions and anti-tumor humoral responses

B cells mature into antibody-secreting cells by antigen processing and presentation and undergo productive germinal center (GC) reactions in secondary lymphoid organs. In solid tumors, antigen presentation and local anti-tumor humoral immunity can arise through the formation of GC-like tertiary lymphoid structures (TLS). Here, we show that cathepsin S activity is essential to form mature GC and TLS by regulating the communication of B cells with CD4⁺ Tfh cells and follicular dendritic cells. The absence of cathepsin S activity impairs B cells’ affinity maturation and high-affinity antibody production, and it limits the formation of TLS in lung and colorectal cancers, accelerating tumor progression. Conversely, the expression of an overactive form of cathepsin S, CTSS^Y132D, which was identified in follicular lymphoma patients, induces an accumulation of proliferating GC B cells, predisposing to lymphoma development. Overall, cathepsin S plays a nonredundant role in B cells, where maintaining its balanced activity is crucial to prevent lymphomagenesis and develop effective humoral immune responses.