The Fas-FasL system: from apoptosis regulator to therapeutic target in autoimmunity, cancer, and transplantation.

The Fas-FasL system is a central regulator of apoptosis, immune homeostasis, and tissue equilibrium. This pathway is mediated by Fas (CD95/APO-1) and its ligand FasL (CD95L/APO-1 L), which upon interaction assemble the death-inducing signaling complex (DISC) and initiate downstream signaling cascades that can result in apoptosis or non-apoptotic immune responses. Dysregulation of this pathway contributes to diverse pathologies. Impaired expression or signaling of Fas or FasL disrupts the elimination of autoreactive lymphocytes, undermining self-tolerance and promoting autoimmune disease. Fas-FasL interactions also play a critical role in balancing effector and regulatory T-cell responses. These insights have driven interest in combination therapies that modulate Fas signaling alongside immunosuppressive agents to enhance efficacy while minimizing toxicity. Future therapeutic strategies will require selective targeting of disease-specific Fas/FasL-expressing cells to avoid damage to healthy tissues. Advances in targeted delivery platforms, including nanoparticles and antibody-based carriers, may improve this specificity. Continued investigation into how Fas-FasL integrates with other immune checkpoints, such as PD-1/PD-L1 and CTLA-4, will be essential for designing synergistic immunomodulatory approaches. Collectively, this review highlights the multifaceted roles of the Fas-FasL pathway and its emerging therapeutic potential in cancer, autoimmune disorders, and allograft tolerance.