Targeting PD-L2: Enhancing Chemotherapy Efficacy by Overcoming Senescence-Induced Immunosuppression

This study highlights how chemotherapy-induced senescent cancer cells hinder treatment by modifying the tumor microenvironment and promoting immunosuppression via upregulated expression of the immune checkpoint ligand PD-L2. While PD-L2 is unnecessary for senescence induction, it enables senescent cells to evade immune surveillance. Experiments revealed that PD-L2-deficient cancer cells are efficiently eliminated post-chemotherapy, with reduced secretion of CXCL1 and CXCL2 chemokines, failure to recruit myeloid-derived suppressor cells, and enhanced CD8+ T-cell-driven tumor regression. Combining chemotherapy with PD-L2 blockade in mouse models of mammary tumors led to significant tumor remission. These findings suggest that targeting PD-L2 alongside chemotherapy could exploit vulnerabilities created by therapy-induced senescence, offering a promising strategy to overcome tumor resistance and improve outcomes.