<p>Despite the clinical success of immune checkpoint blockade therapy, most persons do not benefit because of inadequate efficacy, primary or acquired resistance and/or immune-related toxicities. Here we developed an erythrocyte–antibody conjugate in which anti-PD1 antibodies are covalently linked to erythrocyte membranes (αPD1-Ery). Unlike conventional antibodies, αPD1-Ery accumulates in the spleen, where it remodels the immune landscape by expanding effector T cells and reducing immunosuppressive myeloid cells. These changes reprogram the tumor microenvironment and suppress tumor growth in syngeneic mouse models. We conducted a first-in-human, phase 1 clinical trial of αPD1-Ery monotherapy in persons with advanced cancers resistant to prior anti-PD1/PDL1 therapy (<a href="https://clinicaltrials.gov/ct2/show/NCT03690193">NCT06026605</a>). The primary objective was safety; secondary objectives included efficacy, pharmacokinetics, pharmacodynamics and immunogenicity. A total of 14 participants were enrolled, with 7 receiving 2 × 10¹¹ cells and 7 receiving 3 × 10¹¹ cells. Repeated administration resulted in no dose-limiting toxicities or treatment-related adverse events of grade &gt;3. The objective response rate was 42.9%, including 1 complete response and 5 partial responses; disease control rate was 78.6%. Notably, αPD1-Ery rapidly reduced circulating immunosuppressive myeloid cells, consistent with preclinical observations. The study met its prespecified primary and secondary endpoints. These findings support spleen-targeted PD1 blockade by erythrocyte–antibody conjugates as a potential strategy for cancer immunotherapy.</p>