Unlocking the mystery of the PD-1/PD-L1 axis: beyond the checkpoint hype

The discovery of the PD-1 receptor and its ligand PD-L1 revolutionized our understanding of immune regulation and, together with that of CTLA-4, allowed the development of immune checkpoint blockade, now a cornerstone of cancer therapy. Early models emphasized a simplistic view in which PD-L1 expression by tumor cells directly inhibited cytotoxic T lymphocytes through PD-1 engagement. However, recent findings reveal that this pathway is far more complex, involving multilayered regulation of PD-L1 expression, extensive post-translational modifications, and a broad spectrum of interacting partners. In addition to tumor cells, multiple immune and stromal populations, including dendritic cells, macrophages, T cells, and endothelial cells, express PD-L1 and critically shape anti-tumor immunity and therapeutic responses. Moreover, PD-L1 exerts intrinsic, non-immune functions within tumor cells, including regulation of proliferation, apoptosis resistance, and metabolic adaptation. PD-1 itself, long viewed as a T-cell-restricted inhibitory receptor, is now recognized as functionally relevant on additional cell types such as natural killer cells, myeloid cells, and even tumor cells, further diversifying its role in immune regulation and tumor biology. Together, these insights challenge the classical dogma and call for a refined view of the PD-1/PD-L1 axis that accounts for its cellular heterogeneity, molecular complexity, and bidirectional signalling. Incorporating this knowledge into clinical practice will be essential to improve patient stratification, overcome therapeutic resistance, and design innovative combination strategies to fully exploit the potential of immune checkpoint blockade.