Topic: Targeting the Cancer Cell Surfaceome in Radioligand Therapy Resistance: Mechanisms of Resistance and Therapeutic Adaptation

Cell surface proteins are central therapeutic targets across many cancer types. Radioligand therapies (RLT) depend on adequate and persistent expression of the cell-surface protein target. Resistance and acquired treatment failure may result from antigen loss, reduced antigen density, tumor heterogeneity, genomic alterations, altered internalization and trafficking, changes in DNA damage response and repair capacity, and lineage plasticity. As RLT becomes increasingly integrated into clinical practice, understanding how target protein expression changes during treatment and how these changes influence subsequent therapeutic options is becoming increasingly important. The growing availability of multiple radioligand agents and radionuclides directed against the same or related antigens also raises important questions regarding biomarker selection, cross-resistance, treatment sequencing, and the optimal use of combination approaches.

This Special Topic issue will bring together clinical, translational, and mechanistic studies of RLT resistance across tumor types and therapeutic settings. We welcome studies addressing mechanisms and predictive biomarkers of RLT resistance, antigen heterogeneity and evolution, molecular and imaging-based assessment of target protein expression, patient selection, treatment sequencing and cross-resistance, and strategies to improve therapeutic efficacy through target-informed treatment adaptation, rational combinations, and alternative radionuclide or target strategies designed to overcome treatment failure of RLT.

Topics of interest include, but are not limited to:

● Mechanisms of RLT resistance: antigen loss and downregulation, altered internalization and trafficking, tumor heterogeneity, genomic alterations, lineage plasticity, and other tumor-intrinsic mechanisms;

● Radiobiology and DNA damage response: absorbed dose and dosimetry, dose heterogeneity, DNA damage response and repair capacity, and determinants of radiobiological sensitivity;

● Tumor microenvironment and resistance: hypoxia, stromal and immune interactions, and other microenvironmental factors influencing RLT efficacy;

● Predictive biomarkers and treatment monitoring: molecular imaging, quantitative imaging, liquid biopsy, circulating tumor cells, target expression dynamics, and companion diagnostics;

● Preclinical models of RLT resistance, including patient-derived xenografts, organoids, and engineered resistant models;

● Therapeutic adaptation and overcoming resistance: treatment sequencing, cross resistance, alternative radionuclides, target switching, dual or multispecific targeting approaches, rational combinations, and antigen/target re-induction;

● Transcriptional, epigenetic, and post-translational regulation of target expression, and pharmacologic strategies to restore or enhance target expression;

● Emerging strategies to overcome RLT resistance, including combination approaches with DNA damage response inhibitors, immunotherapy, and other targeted therapies.