ACP3 Theranostics in Prostate Cancer

Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) and radioligand therapy have established a major clinical paradigm for prostate cancer theranostics. Their performance is influenced by interpatient and interlesional heterogeneity, treatment-related changes in PSMA expression, and physiological ligand uptake in organs such as the salivary glands and kidneys, creating a rationale for complementary targets with different lesion coverage and normal-tissue distribution. ACP3 (acid phosphatase 3; historical symbol ACPP) encodes prostatic acid phosphatase (PAP), which is also termed prostate-specific acid phosphatase (PSAP) in older pathology literature. PAP has served as a serum biomarker, an immunohistochemical marker of prostatic origin, and an immunotherapeutic antigen. DNA-encoded library screening identified the high-affinity PAP ligand OncoACP3, and the resulting [177Lu]Lu-OncoACP3-DOTAGA radioligand and OncoACP3-GlyPro-MMAE small-molecule drug conjugate achieved target-dependent payload delivery and antitumor activity in preclinical models. First-in-human PET and subsequent pharmacokinetic and diagnostic dosimetry studies of [68Ga]Ga-OncoACP3-DOTA demonstrated visualization of localized and metastatic prostate cancer lesions and a normal-organ distribution distinct from that of PSMA-targeted ligands. This narrative review synthesizes the molecular characteristics and biological functions of PAP, historical clinical applications, and modern ACP3-targeted imaging and therapeutic platforms. Existing studies now provide a biological foundation, preclinical proof of targeted payload delivery, and early human imaging, pharmacokinetic, and diagnostic-dosimetry evidence. Prospective development should next define the ligand-accessible PAP pool, imaging-positivity criteria, therapeutic dosimetry, and the patient groups in whom ACP3 adds value to the PSMA theranostic framework.