Beyond treatment eligibility: rethinking theranostic targets

Abstract

Theranostics occupies a unique position in oncology because the same molecular target simultaneously enables disease visualization and therapeutic delivery. Unlike most anticancer strategies, where biomarkers primarily determine treatment eligibility, theranostic targets directly connect molecular imaging with targeted radionuclide therapy, making them the biological foundation of the theranostic paradigm. This target-driven paradigm has transformed the management of several malignancies and established theranostics as one of the most successful examples of precision oncology (1,2).Consequently, theranostic targets have traditionally been regarded as gatekeepers to treatment.Demonstrating sufficient target expression before therapy remains the cornerstone of patient selection and underpins current international recommendations for theranostic radioligand therapies (3,4). This paradigm has been remarkably successful but has largely focused attention on the presence of a target before treatment initiation.Recent advances in tumor biology, however, suggest that this view may be incomplete. Molecular target expression is increasingly recognized as a dynamic biological phenotype shaped by intrapatient heterogeneity, clonal evolution, therapeutic pressure and treatment-induced modulation rather than a fixed characteristic of the disease (5). In prostate cancer, longitudinal imaging studies have demonstrated that PSMA expression can change rapidly following androgen receptor pathway inhibition, with substantial variability observed between metastatic lesions within the same patient (6).Likewise, the PSMA flare phenomenon illustrates that temporal variations in tracer uptake may reflect biological adaptation rather than simply changes in tumor burden (7).These observations invite a fundamental reconsideration of the role assigned to theranostic targets. Should molecular targets continue to be viewed primarily as biomarkers defining treatment eligibility, or should they increasingly be regarded as dynamic biological systems whose temporal evolution provides biologically meaningful information? We propose that theranostic targets should be viewed not only as biomarkers guiding treatment decisions, but also as dynamic biological entities whose longitudinal evolution may provide biologically meaningful information throughout the course of disease and therapy. Importantly, this perspective should not be confused with conventional treatment monitoring or response assessment. Whereas response assessment primarily seeks to determine whether therapy is effective by evaluating changes in tumor burden or disease progression, the present concept considers the therapeutic target itself as the primary object of biological investigation. In this framework, serial molecular imaging is viewed not only as a tool for evaluating treatment efficacy, but also as a means of characterizing longitudinal changes in therapeutic target biology under therapeutic pressure.In this Opinion, we discuss how recent advances in target biology support this conceptual shift and explore its potential implications for the future development of theranostics.The remarkable success of theranostics has been built upon the identification of molecular targets capable of selecting patients for radionuclide therapy. Consequently, clinical practice has naturally focused on confirming sufficient target expression before treatment initiation, establishing molecular imaging as the gateway to therapy (3,4). This approach has transformed patient care and remains the cornerstone of contemporary theranostic practice. However, it has also largely confined the biological role of theranostic targets to a single time point: treatment eligibility.Emerging evidence, however, suggests that this view is incomplete. Rather than representing immutable features of cancer cells, molecular targets are increasingly recognized as dynamic biological phenotypes shaped by tumor differentiation, clonal evolu