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

Purpose: Targeted radionuclide therapy with 177 Lu-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 177 Lu-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 177 Lu-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.