Chemotherapy often generates intratumoral senescent cancer cells that modify the tumor microenvironment, promoting immunosuppression and tumor growth. This study shows that the immune checkpoint inhibitor PD-L2 is highly upregulated in senescent cancer cells. PD-L2 is not required for senescence but is critical for senescent cells to evade the immune system and persist intratumorally. PD-L2-deficient senescent cancer cells are rapidly eliminated after chemotherapy, leading to reduced tumor growth and increased CD8 T cell activity. Anti-PD-L2 antibodies synergize with chemotherapy to induce remission in mammary tumors. PD-L2 is expressed by various immune cells and contributes to immunosuppression in cancer. PD-L2 is upregulated in response to chemotherapy and is involved in the recruitment of myeloid-derived suppressor cells (MDSCs), which promote tumor growth. PD-L2 deficiency reduces MDSC recruitment and enhances immune surveillance. PD-L2 is not required for cellular senescence but is essential for immune evasion. PD-L2-deficient tumors are more susceptible to chemotherapy and show reduced tumor growth. PD-L2 expression is associated with the persistence of senescent cells and the secretion of immunosuppressive factors. Anti-PD-L2 therapy combined with chemotherapy improves immune surveillance and tumor control. PD-L2 is a potential therapeutic target for enhancing the efficacy of cancer treatments. The study highlights the role of PD-L2 in therapy-induced senescence and its impact on tumor immunosurveillance.Chemotherapy often generates intratumoral senescent cancer cells that modify the tumor microenvironment, promoting immunosuppression and tumor growth. This study shows that the immune checkpoint inhibitor PD-L2 is highly upregulated in senescent cancer cells. PD-L2 is not required for senescence but is critical for senescent cells to evade the immune system and persist intratumorally. PD-L2-deficient senescent cancer cells are rapidly eliminated after chemotherapy, leading to reduced tumor growth and increased CD8 T cell activity. Anti-PD-L2 antibodies synergize with chemotherapy to induce remission in mammary tumors. PD-L2 is expressed by various immune cells and contributes to immunosuppression in cancer. PD-L2 is upregulated in response to chemotherapy and is involved in the recruitment of myeloid-derived suppressor cells (MDSCs), which promote tumor growth. PD-L2 deficiency reduces MDSC recruitment and enhances immune surveillance. PD-L2 is not required for cellular senescence but is essential for immune evasion. PD-L2-deficient tumors are more susceptible to chemotherapy and show reduced tumor growth. PD-L2 expression is associated with the persistence of senescent cells and the secretion of immunosuppressive factors. Anti-PD-L2 therapy combined with chemotherapy improves immune surveillance and tumor control. PD-L2 is a potential therapeutic target for enhancing the efficacy of cancer treatments. The study highlights the role of PD-L2 in therapy-induced senescence and its impact on tumor immunosurveillance.