Abstract Metastatic castration-resistant prostate cancer (mCRPC) remains a major cause of cancer-related mortality in the male population. While poly(ADP-ribose) polymeraseinhibitors (PARPi) are approved for selected mCRPC patients with homologous recombination repair (HRR) deficiencies, combinations with PD-1/PD-L1 inhibitors immunotherapy have demonstrated limited efficacy in unselected populations. To investigate the immunomodulatory effects of PARPi in an unbiased manner, we performed bulk RNA sequencing on HRR-proficient MyC-CaP cells treated with PARPi Olaparib or control vehicle. Pathway enrichment analysis revealed a marked upregulation of CD73 (NT5E), an emerging immune checkpoint ectoenzyme that generates extracellular adenosine, suggesting an adaptive mechanism that undermines PARPi efficacy and enables unwanted immunosuppression. CD73 induction by PARPi was confirmed in both human and mouse prostate cancer cell lines, with more pronounced effects in the HRR-compromised PTEN knock-out (KO) cells. Mechanistically, Olaparib-driven CD73 expression was mediated through the DNA damage-activated ATR-CHEK1-IRF1 and TGF-β1-ΑΚΤ signaling pathways. Concurrently, PARPi enhanced tumor cell immunogenicity by activating the type I interferon pathway and antigen presentation machinery. In vivo, combining Olaparib with CD73 blockade therapy delayed tumor growth, improved T-cell infiltration, and augmented antigen-specific CD8+ T-cell effector function across HRR-proficient and PTEN KO prostate cancer models. These findings highlight PARPi-induced CD73 upregulation as a novel resistance mechanism and support PARPi plus CD73 blockade as a promising therapeutic strategy for mCRPC, irrespective of HRR status. Citation Format: Ping xie, Jie Fan, Hui Tang, Longzhen Song, Bin Zhang. Adaptive cd73 upregulation undermines parp inhibitor efficacy and creates a therapeutic opportunity for combined blockade in advanced prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3802.
Xie et al. (Fri,) studied this question.