Prostate-specific membrane antigen (PSMA) is an important cell-surface imaging biomarker and therapeutic target in prostate cancer. The PSMA-targeted theranostic ¹⁷⁷Lu-PSMA-617 was approved in 2022 for men with PSMA-PET-positive metastatic castration-resistant prostate cancer. However, not all patients respond to PSMA-radioligand therapy, in part owing to the heterogeneity of PSMA expression in the tumour. The PSMA regulatory network is composed of a PSMA transcription complex, an upstream enhancer that loops to the FOLH1 (PSMA) gene promoter, intergenic enhancers and differentially methylated regions. Our understanding of the PSMA regulatory network and the mechanisms underlying PSMA suppression is evolving. Clinically, molecular imaging provides a unique window into PSMA dynamics that occur on therapy and with disease progression, although challenges arise owing to the limited resolution of PET. PSMA regulation and heterogeneity — including intertumoural and inter-patient heterogeneity, temporal changes, lineage dynamics and the tumour microenvironment — affect PSMA theranostics. PSMA response and resistance to radioligand therapy are mediated by a number of potential mechanisms, and complementary biomarkers beyond PSMA are under development. Understanding the biological determinants of cell surface target regulation and heterogeneity can inform precision medicine approaches to PSMA theranostics as well as other emerging therapies.

前列腺特异性膜抗原 （PSMA） 是前列腺癌中重要的细胞表面成像生物标志物和治疗靶点。PSMA 靶向治疗诊断学 ¹⁷⁷Lu-PSMA-617 于 2022 年被批准用于 PSMA-PET 阳性转移性去势抵抗性前列腺癌男性患者。然而，并非所有患者都对 PSMA 放射配体治疗有反应，部分原因是 PSMA 在肿瘤中表达的异质性。PSMA 调节网络由 PSMA 转录复合物、循环至 FOLH1 （PSMA） 基因启动子的上游增强子、基因间增强子和差异甲基化区域组成。我们对 PSMA 调节网络和 PSMA 抑制机制的理解正在不断发展。在临床上，分子成像为了解治疗中和疾病进展发生的 PSMA 动力学提供了一个独特的窗口，尽管由于 PET 的分辨率有限而存在挑战。PSMA 调节和异质性 — 包括肿瘤间和患者间异质性、时间变化、谱系动力学和肿瘤微环境 — 影响 PSMA 治疗诊断学。PSMA 反应和对放射配体治疗的耐药性是由许多潜在机制介导的，PSMA 以外的互补生物标志物正在开发中。了解细胞表面靶标调控和异质性的生物学决定因素可以为 PSMA 治疗诊断学以及其他新兴疗法的精准医学方法提供信息。