Radiopharmaceutical Therapy–Linked Tumor Resistance: Immune Evasion, Nonimmune Mechanisms, and Immunometabolic Vulnerabilities

Radiopharmaceutical therapy (RPT) has transformed the management of metastatic castration-resistant prostate cancer and neuroendocrine tumors, with clinical development extending to renal cell carcinoma, hepatocellular carcinoma, lung cancer, and breast cancer. Because relapse after RPT occurs across cancer types, there is an urgent need to implement new treatment strategies to overcome resistance and achieve more durable responses. Here, we summarize recent advances in research concerning RPT resistance mechanisms involving tumor cell-intrinsic signaling, the tumor immune microenvironment, and tumor metabolism, as well as emerging strategies to overcome them. We also highlight progress in advanced preclinical models that better recapitulate human metabolism and immune responses, which are essential for validating new combination approaches designed to maximize the clinical benefit of RPT, with a focus on prostate cancer.