Bidirectional regulation of the PD-1 pathway: Tumor immune exhaustion versus lupus nephritis T cells activation.

The PD-1/PD-L1 immune checkpoint pathway serves as a core regulatory hub that maintains peripheral immune tolerance. In different disease contexts, this axis exhibits opposing outcomes. In cancer, sustained antigenic stimulation elevates PD-1 expression and locks T cells into an exhaustion phenotype-a state characterized by progressive loss of effector functions, coordinated upregulation of multiple inhibitory receptors, and a TOX-driven epigenetic landscape. Conversely, in lupus nephritis (LN)-a severe autoimmune complication of systemic lupus erythematosus (SLE)-PD-1+ T cells (both CD8+ and CD4+ subsets) undergo clonal expansion, display a highly activated phenotype, and produce abundant granzyme B, perforin, and IFN-γ, thereby directly inflicting renal tissue damage. Importantly, LN-associated PD-1+ T cells are not uniformly exhausted; single-cell studies suggest that activated and partially exhausted subsets can co-exist. This review systematically elucidates the molecular, cellular, and microenvironmental bases that determine the bidirectional nature of PD-1 signaling-driving T cells toward exhaustion in cancer while promoting T cell activation in LN. Key differentiating factors underlying this divergence include the intensity and persistence of antigen stimulation, activation of the TOX-dependent exhaustion epigenetic program, the cytokine milieu composition (type I interferons, IL-12, IL-6), the balance between co-stimulatory and co-inhibitory signals, and the strikingly different metabolic environments-a nutrient-deprived, hypoxic tumor microenvironment versus an inflamed, metabolically active kidney in LN. As a theoretical synthesis, we propose a conceptual "balancing window" model of PD-1 signal strength to describe this bidirectional regulatory mechanism; this model is hypothesis-generating and not clinically validated. Finally, we discuss the clinical translation implications of this framework, encompassing PD-1 agonistic strategies in autoimmune diseases (still largely preclinical/early clinical), PD-1 blockade in cancer therapy, and the iatrogenic lupus-like syndrome induced by immune checkpoint inhibitors-the latter providing biological plausibility rather than definitive proof of causality. All proposed biomarkers and algorithms are presented as investigational tools not yet ready for routine clinical practice. Moreover, LN pathogenesis involves multiple pathways beyond T cells-including immune complexes, complement, B cells, and innate immunity-and the PD-1 axis should be considered within this broader context.

The PD-1/PD-L1 immune checkpoint pathway serves as a core regulatory hub that maintains peripheral immune tolerance. In different disease contexts, this axis exhibits opposing outcomes. In cancer, sustained antigenic stimulation elevates PD-1 expression and locks T cells into an exhaustion phenotype-a state characterized by progressive loss of effector functions, coordinated upregulation of multiple inhibitory receptors, and a TOX-driven epigenetic landscape. Conversely, in lupus nephritis (LN)-a severe autoimmune complication of systemic lupus erythematosus (SLE)-PD-1+ T cells (both CD8+ and CD4+ subsets) undergo clonal expansion, display a highly activated phenotype, and produce abundant granzyme B, perforin, and IFN-γ, thereby directly inflicting renal tissue damage. Importantly, LN-associated PD-1+ T cells are not uniformly exhausted; single-cell studies suggest that activated and partially exhausted subsets can co-exist. This review systematically elucidates the molecular, cellular, and microenvironmental bases that determine the bidirectional nature of PD-1 signaling-driving T cells toward exhaustion in cancer while promoting T cell activation in LN. Key differentiating factors underlying this divergence include the intensity and persistence of antigen stimulation, activation of the TOX-dependent exhaustion epigenetic program, the cytokine milieu composition (type I interferons, IL-12, IL-6), the balance between co-stimulatory and co-inhibitory signals, and the strikingly different metabolic environments-a nutrient-deprived, hypoxic tumor microenvironment versus an inflamed, metabolically active kidney in LN. As a theoretical synthesis, we propose a conceptual "balancing window" model of PD-1 signal strength to describe this bidirectional regulatory mechanism; this model is hypothesis-generating and not clinically validated. Finally, we discuss the clinical translation implications of this framework, encompassing PD-1 agonistic strategies in autoimmune diseases (still largely preclinical/early clinical), PD-1 blockade in cancer therapy, and the iatrogenic lupus-like syndrome induced by immune checkpoint inhibitors-the latter providing biological plausibility rather than definitive proof of causality. All proposed biomarkers and algorithms are presented as investigational tools not yet ready for routine clinical practice. Moreover, LN pathogenesis involves multiple pathways beyond T cells-including immune complexes, complement, B cells, and innate immunity-and the PD-1 axis should be considered within this broader context.