To address the issue of PD-1 inhibitor resistance driven by the immunosuppressive tumor microenvironment in triple-negative breast cancer (TNBC), we constructed activated platelet membrane-derived vesicles for targeted delivery of hemopexin (HPX) small interfering RNA (siRNA) (APP@siHPX), which effectively reduced the extracellular transport of heme and inhibited heme-mediated thrombospondin-1 (TSP-1) release, leading to decreased tumor-associated macrophage (TAM) recruitment and reprogramming of TAMs from the M2 phenotype to the M1 phenotype. Consequently, combining APP@siHPX with PD-1 inhibitors synergistically alleviates T-cell immunosuppression and increases CD8⁺ T-cell activity, resulting in significant tumor growth inhibition. In summary, our results demonstrate that targeting the HPX-heme-TSP-1 axis via APP@siHPX represents a promising strategy for enhancing the efficacy of immune checkpoint inhibitors in TNBC.