Divergent Expression of PD-1 as Challenges and Chances of Immunotherapy Targeting PD-1 or PD-L1 in Cancer

The effectiveness of programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) immunotherapies in cancer treatment is significantly influenced by the variable expression levels of PD-1/PD-L1. The determinants of PD-1/PD-L1 expression variability remain elusive, posing substantial challenges to therapeutic strategy development. This review delves into the PD-1/PD-L1 pathway, exploring its physiological functions, expression disparities in primary versus metastatic tumours, heterogeneity across cancer types, and its role in T-cell activation. It also evaluates alternative strategies for enhancing T-cell activity. The discrepancy in therapeutic outcomes is largely ascribed to tumour genetic diversity, which dictates PD-1/PD-L1 expression levels. This necessitates a deeper understanding of the underlying mechanisms or exploring additional checkpoint inhibitors as potential targets to surmount the limitations posed by PD-1/PD-L1 expression variability.