Interplays Between Therapeutic Radiopharmaceuticals and Tumor Microenvironment

Radiopharmaceuticals have progressed from diagnostic agents toward theranostic. With the accelerating development of therapeutic radiopharmaceuticals, radiopharmaceutical therapy (RPT) is being increasingly implemented in clinical practice in oncology. However, current therapeutic radiopharmaceuticals often contribute to tumor stabilization rather than complete remission. A major determinant of this limited clinical response is the tumor microenvironment (TME), which critically influences the delivery, penetration, and retention of radiopharmaceuticals. Meanwhile, the radiopharmaceuticals can modulate multiple components of the TME, thereby contributing to antitumor effects. These interactions provide opportunities for advancing radiopharmaceuticals to enhance RPT efficacy. In this review, the bidirectional relationship between therapeutic radiopharmaceuticals and TME in solid malignancies is comprehensively discussed. First, common therapeutic strategies that modulate TME are outlined. The impact of the TME on radiopharmaceutical efficacies and how radiopharmaceuticals reshape the TME are then highlighted. In addition to elucidating the bidirectional interplay between RPT and the TME, we examine two fundamental clinical barriers that constrain RPT efficacy: dosimetric limitations and systemic immune collateral damage. Finally, critical challenges and potential strategies to enhance next-generation therapeutic radiopharmaceuticals in solid malignancies are inspected.