Bridging B-cell autoimmunity and oncology: the PD-1/PD-L1 paradox in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) remains one of the most challenging autoimmune diseases due to its complex pathogenesis involving the breakdown of B cell tolerance. While the PD-1/PD-L1 axis is traditionally viewed as a universal inhibitory checkpoint, its role in SLE is uniquely nuanced. In this review, we synthesize recent findings to clarify the "PD-1 Paradox"-the observation that high PD-1 expression on pathogenic T follicular helper (Tfh) and T peripheral helper (Tph) cells in SLE patients correlates with chronic activation and extrafollicular expansion rather than functional exhaustion. We also summarize emerging precision immunotherapy strategies, including PD-1 agonists, bispecific inhibitors (targeting ICOSL/BAFF), and engineered mesenchymal stem cells (MSCs). These interventions aim to move beyond traditional immunosuppression toward a precision "reset" of the autoimmune system.