| 描述信息 |
Despite the success of immune checkpoint blockade therapy, its efficacy remains limited for many patients due to resistance. While the peripheral immune system is crucial in anti-tumor immunity, it can also be manipulated by cancer to facilitate tumor growth. Here, we developed an erythrocyte-anti-PD-1 antibody conjugate or αPD-1-Ery, where FDA-approved Pembrolizumab is covalently linked to erythrocyte membranes. Unlike conventional antibodies, αPD-1-Ery naturally accumulates in the spleen and remodels the local immune landscape by reducing immunosuppressive cells and expanding T cells in tumor-bearing mice. Treatment with αPD-1-Ery suppresses tumor growth in xenograft models resistant to anti-PD-1 therapy, dependent on spleen function. Furthermore, activated T cells by αPD-1-Ery reduce the splenic reservoir of myeloid suppressive cells and those within tumors, thereby enhancing anti-tumor immunity. In a clinical trial, autologous transfusion of αPD-1-Ery effectively reduces tumor growth in heavily treated cancer patients with resistance to anti-PD-1 therapies while maintaining safety. This result correlates with reductions in circulating myeloid suppressive cells and expansion of effector T cell subtypes. Our study suggests potential therapeutic strategies by targeting the peripheral immune system for overcoming immune checkpoint blockage resistance in cancer treatment. |
