Hemoglobin-Based Oxygen Carriers Promoted the Antitumor Effect of 177Lu-PSMA-617 by Enhancing DNA Repair Capacity of Immune Cells.

Purpose: Targeted radionuclide therapy with 177Lu-PSMA-617 prolongs radiographical progression-free survival in prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC), yet 13% of patients develop symptomatic skeletal events. The authors hypothesized that hemoglobin-based oxygen carriers (HBOCs) could potentiate 177Lu-PSMA-617 by reprogramming bone marrow (BM) immunity.Methods:Using PSMA-expressing xenografts, they demonstrated that concomitant HBOC administration significantly reduced tumor volume without increasing systemic toxicity. To dissect the underlying mechanism, the authors performed high-resolution single-cell RNA sequencing of murine BM.Results:HBOC treatment markedly expanded mature neutrophils, plasmacytoid dendritic cells, classical monocytes, natural killer T cells, and mature B cells, while concomitantly upregulating DNA damage repair genes such as Parp9, Dtx3l, and Smchd1 within these subsets. Gene set enrichment analysis confirmed significant activation of DNA damage response pathways, implying enhanced cellular radioresistance and improved tolerance to β-particle irradiation.Conclusions: Thus, HBOCs improve 177Lu-PSMA-617 antitumor efficacy indirectly via immune-subset expansion and DNA-repair reinforcement, offering a clinically feasible and safe strategy to optimize combination protocols for patients with mCRPC.