Abstract Background: Chronic lymphocytic leukemia (CLL) and systemic lupus erythematosus (SLE) represent opposing failures of immune regulation—tumor-driven suppression versus unchecked autoreactivity—yet both exploit the BAFF/APRIL–TACI (TNFRSF13B) axis. Continuous TACI engagement activates NF-κB signaling, promoting leukemic cell survival and rescuing autoreactive B cells from deletion. While therapies such as BTK and BCL-2 inhibitors shrink CLL tumors, they often impair immune competence; similarly, broad B-cell depletion in SLE curbs autoantibodies but heightens infection risk. A strategy that dismantles pathogenic B-cell programs while sparing protective immunity remains urgently needed. Aim: To assess whether genetic or antibody-mediated TACI blockade (i) suppresses CLL progression and restores anti-tumor immunity, and (ii) re-establishes self-tolerance across lupus models. Methods: Cancer arm: Eµ-TCL1 CLL cells, with or without TACI, were transplanted into wild-type mice (n ≥ 4/group); tumor burden, cytokines, and T-cell subsets were analyzed by flow cytometry. Microarray and real-time PCR profiled the transcriptional impact of TACI loss. Primary human CLL samples (≥ 4) underwent migration assays, T-cell co-culture ± anti-TACI antibody, and CRISPR-mediated TACI knockdown before NSG mouse engraftment. Autoimmunity arm: TACI deletion was introduced into BAFF-Tg, Lyn-/-, and Sanroque mice (n ≥ 4/strain). Plasma-cell frequencies, germinal-center dynamics, Tfh activity, autoantibody titers, renal pathology, and serum cytokines were assessed. Safety endpoints included weight, hematology, and vaccine-response assays. Results: TACI loss restrained pathogenic B-cell programs across both disease contexts. In CLL, mice engrafted with TACI-/- cells showed delayed disease progression, lower tumor incidence, normalized IL-6/IL-10 levels, and restored T-cell subsets versus TACI+/+ controls. TACI-deficient CLL cells downregulated IL-10, TNF, PD-L1, and PD-L2, restored immunoglobulin levels, and re-established T-cell–dependent antigen responses. Mechanistically, TACI enhanced CLL cell migration and splenic homing, promoting an immunosuppressive microenvironment; findings were validated in primary CLL cells and PDX models. In lupus models, TACI deletion restored B-cell homeostasis. BAFF-Tg TACI-/- mice exhibited normal plasma-cell frequencies and reduced autoantibodies and IFN-γ. Lyn-/- TACI-/- mice showed fewer plasma cells, lower cytokine production, and preserved renal structure. Sanroque TACI-/- mice displayed corrected Tfh activity and normalized autoantibody levels. Protective immune responses were maintained across all models without overt immunodeficiency. Conclusion: TACI blockade restores immune balance by impairing leukemic B-cell survival and migration while preserving humoral responses. Simultaneously, it re-establishes tolerance and prevents end-organ damage in lupus. These findings support TACI inhibition as a cross-disease therapeutic strategy unifying cancer immunotherapy and autoimmunity control. Citation Format: Yong Sheng, Beatriz Garcillán, M Arifur Rahman, William A. Figgett, SiLing Yang, Yukli Freedman, Eden H. Whitlock, Nicholas H. Weber, Fabienne Mackay. Disrupting TACI signaling to restore immune balance: harnessing translational opportunities at the intersection of cancer and autoimmunity abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr PR-06.
Sheng et al. (Wed,) studied this question.