Context-dependent immunoregulation by BAFF: reconciling its pro-tumorigenic, anti-tumor, and autoimmune roles through a multi-factorial lens
5 affiliations
- 1The First Affiliated Hospital of Dalian Medical University
- 2Dalian Medical University
- 3Department of Urology, First Hospital of Shanxi Medical University
- 4Department of Gastroenterology, Shengjing Hospital of China Medical University
- 5Department of Cardiology, Dandong First Hospital
Abstract
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.
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BibTeX
@article{shang2026contextdependent,
title = {{Context-dependent immunoregulation by BAFF: reconciling its pro-tumorigenic, anti-tumor, and autoimmune roles through a multi-factorial lens}},
author = {Jiayi Shang and Minli Jin and Kui Jiang and Weiqi Liu and Jinji Li and Xiaochi Chen},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1975879},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1975879/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Context-dependent immunoregulation by BAFF: reconciling its pro-tumorigenic, anti-tumor, and autoimmune roles through a multi-factorial lens
AU - Jiayi Shang
AU - Minli Jin
AU - Kui Jiang
AU - Weiqi Liu
AU - Jinji Li
AU - Xiaochi Chen
PY - 2026
DA - 2026/10/28
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1975879
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1975879/full
AB - 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.
SN - 1664-3224
ER -