The study investigates the role of programmed cell death 1 ligand 2 (PD-L2) in the efficacy of chemotherapy for cancer. Chemotherapy often induces intratumoral senescent cancer cells, which modify the tumor microenvironment to favor immunosuppression and tumor growth. The research team discovered that PD-L2 is highly upregulated in senescent cancer cells across various cancer types, despite not being essential for the induction of senescence. PD-L2 is critical for the persistence of senescent cells in the tumor microenvironment, as PD-L2-deficient senescent cells are rapidly eliminated after chemotherapy, leading to reduced tumor growth and the production of senescence-associated chemokines CXCL1 and CXCL2. In mouse models, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Additionally, combining chemotherapy with anti-PD-L2 antibodies strongly synergizes with chemotherapy, causing remission in mammary tumors in mice. These findings suggest that targeting PD-L2 can enhance the efficacy of chemotherapy by exploiting vulnerabilities arising from therapy-induced senescence.The study investigates the role of programmed cell death 1 ligand 2 (PD-L2) in the efficacy of chemotherapy for cancer. Chemotherapy often induces intratumoral senescent cancer cells, which modify the tumor microenvironment to favor immunosuppression and tumor growth. The research team discovered that PD-L2 is highly upregulated in senescent cancer cells across various cancer types, despite not being essential for the induction of senescence. PD-L2 is critical for the persistence of senescent cells in the tumor microenvironment, as PD-L2-deficient senescent cells are rapidly eliminated after chemotherapy, leading to reduced tumor growth and the production of senescence-associated chemokines CXCL1 and CXCL2. In mouse models, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Additionally, combining chemotherapy with anti-PD-L2 antibodies strongly synergizes with chemotherapy, causing remission in mammary tumors in mice. These findings suggest that targeting PD-L2 can enhance the efficacy of chemotherapy by exploiting vulnerabilities arising from therapy-induced senescence.