Context-dependent immunoregulation by BAFF: reconciling its pro-tumorigenic, anti-tumor, and autoimmune roles through a multi-factorial lens

B cell activating factor (BAFF), originally characterized as a canonical survival factor for B cells, is now recognized as a pleiotropic immunoregulator that bridges innate and adaptive immunity. Its biological effects are highly context-dependent, manifesting as promotion of malignant B-cell survival in hematological malignancies, conflicting activities in solid tumors, and disruption of B-cell tolerance in autoimmune diseases. Current literature has largely examined BAFF within disease-specific frameworks, leaving cross-disease mechanistic relationships inadequately resolved. In this review, we propose a multi-factorial framework for integrating evidence across cancer and autoimmunity through four proposed variables: ligand concentration, oligomeric form, cellular source, and receptor availability. By dissecting receptor signaling via BAFF receptor (BAFF-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA), we evaluate the therapeutic landscape, safety profiles, and combination strategies of BAFF-targeted agents. The framework is a working hypothesis, not a validated causal model. We propose three integrated perspectives: (i) a proposed multi-factorial framework for interpreting BAFF’s divergent functions; (ii) a conceptual, testable inverted U-shaped working hypothesis for solid tumors, without validated concentration thresholds; and (iii) the translational utility of BAFF system molecules as stratification biomarkers and precision therapeutic targets. Autoimmune disease data provide conceptual support for this concentration-form-context framework, which was initially developed to reconcile contradictory observations in tumors. The framework requires direct experimental titration and oligomer-specific validation. Finally, we identify critical knowledge gaps, including distinct signaling pathways elicited by BAFF oligomers and crosstalk with inflammatory networks, to inform next-generation personalized immunotherapy.