The role of the tumor microenvironment in mediating radiopharmaceutical therapy: bridging nuclear medicine and cancer immunotherapy

Radiopharmaceutical therapy (RPT) is a pivotal modality in cancer treatment, with its efficacy substantially modulated by the tumor microenvironment (TME). The TME regulates RPT penetration and influences therapeutic outcomes. Concurrently, RPT actively reconfigures the TME by enhancing immune activation and partially reversing immunosuppression. Specifically, RPT induces tumor cell senescence and immunogenic cell death, and catalyzes immune activation. RPT diminishes immunosuppressive elements, including regulatory T cells and tumor-associated macrophages, and augments populations of CD8⁺ T cells and natural killer cells, thereby fostering a more immunostimulatory TME. Additionally, RPT modulates critical cytokines and upregulates immune checkpoint molecules, bolstering anti-tumor immunity. Nevertheless, pathological features like hypoxia and extracellular matrix stiffness within the TME can hinder RPT biodistribution and therapeutic efficacy. Strategically targeting the TME through approaches, such as fibroblast depletion, hypoxia mitigation, metabolic reprogramming, nerve-immune-cancer interactions, or nanocarrier drug delivery, can amplify RPT effectiveness. Combination immunotherapies that integrate RPT with immune checkpoint inhibitors, chimeric antigen receptor (CAR)-T cells, or cancer vaccines have demonstrated enhanced anti-tumor responses and survival advantages in malignancies such as prostate cancer and neuroendocrine tumors. Given the complexity and heterogeneity of the TME, emerging strategies, including radiation-responsive nanocarriers, CAR-T cells engineered to secrete radiosensitizers, senolytic therapies, and artificial intelligence-driven multimodal data integration, are promising in addressing the challenges and refining precision cancer therapy. In summary, the TME serves as a critical bridge between RPT and immunotherapy; elucidating the interplay among these three elements is essential for advancing combination strategies.