PD-1-engineered manganese-based nanoplatform loaded with CXCL9 induces ICD and intensifies T-cell infiltration for melanoma treatment

Abstract

Immune checkpoint blockade (ICB) has advanced melanoma therapy, yet its efficacy remains limited by poor tumor immunogenicity and insufficient T-cell infiltration. To overcome these dual barriers, we develop BPC9@MnCO₃, a biomimetic nanoplatform cloaked with PD-1-enriched melanoma membranes and loaded with chemokine CXCL9. The tumor-homing membrane coating directs nanoparticle accumulation in melanoma tissue. Additionally, PD-1 overexpression on the surface of B16-F10 cell membranes blocks the PD-1/PD-L1 signaling axis, thereby restoring T-cell immune function. Within the acidic tumor microenvironment, MnCO₃ decomposes to release Mn²⁺ ions, which trigger immunogenic cell death (ICD) to enhance tumor antigen presentation. Meanwhile, the degradation of MnCO₃ triggers membrane rupture, which increases local CXCL9 levels and leads to enhanced T-cell infiltration, thereby mediating a potent antitumor immune response. Notably, BPC9@MnCO₃ significantly inhibits tumor growth and reduces the number of lung metastases in vivo. These effects are attributed to the ability of BPC9@MnCO₃ to relieve immune checkpoint inhibition and induce ICD effects, effectively improving the immune microenvironment and significantly enhancing T-cell infiltration in tumor tissue. In summary, our work demonstrates a novel strategy to improve ICB efficacy by coordinately targeting immune activation and recruitment barriers.