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, CTSSY132D, 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.