B cells are major players in cancer immunity.

The discovery of Tertiary Lymphoid Structures (TLS) within tumors has reshaped our understanding of cancer immunity. Unlike the classical view that immune responses are solely initiated in lymph nodes, TLS, ectopic lymphoid aggregates resembling secondary lymphoid organs, can form in the tumor microenvironment (TME). These structures contain T cells, B cells, dendritic cells (DC) presenting antigenic peptides to T cells in the T cell zone of TLS, and follicular dendritic cells (FDC) which are stromal cells involved in the formation of germinal centers (GCs) and presenting antigens, under the form of immune complexes, to B cells. Mature TLS with GCs support B cell differentiation into antibody-producing plasma cells (PCs). Clinical studies reveal that TLS presence correlates with improved survival and response to immunotherapy across multiple cancers, including melanoma, NSCLC, and renal cell carcinoma. Notably, B cells within TLS undergo clonal expansion, somatic hypermutation, and isotype switching, generating tumor-reactive antibodies (IgG, IgA). IgG-opsonized tumor cells can be eliminated by macrophages or NK cells via antibody-dependent cell mediated cytotoxicity or apoptosis by macrophages via antibody-dependent phagocytosis whereas IgA may have dual roles, sometimes promoting immunosuppression. Additionally, B cells enhance antigen presentation to T cells, amplifying anti-tumor responses. Emerging strategies aim to induce TLS formation (e.g., via CXCL13, lymphotoxins…) or harness B cells for adoptive therapies. Future research should clarify tumor-specific antibody targets and optimize TLS induction to enhance immunotherapy. In summary, TLS and B cells are pivotal in shaping anti-tumor immunity, offering novel biomarkers and therapeutic avenues for cancer treatment.