Cutaneous T-cell lymphomas (CTCLs) constitute a rare and heterogeneous group of lymphoid malignant neoplasms that initially involve the skin and are considered neglected clinical entities with very limited therapeutic options. Lymphoma cells (both B and T-cells) are extremely radiosensitive compared to solid adenocarcinomas. Nevertheless, many CTCL patients progress to an advanced stage of the disease, in which the malignant cells disseminate through the body, greatly limiting the use of conventional external beam radiotherapy. In the last decade, CD30 emerged as a promising target with high expression on malignant B and T-cells and limited expression in healthy tissues. Thus, recently we have developed radioimmunotherapy (RIT) with anti-CD30 mAbs coupled to radionuclides to selectively deliver high doses of radiation to T-cell lymphomas while preventing radiotoxicity in healthy tissues. Importantly, we have employed novel therapeutic radionuclide Terbium-161, which emits both β--radiation and Auger and conversion electrons with high linear energy transfer and an ultra-short range in tissue. Currently, it is important to understand how this type of RIT with Tb-161 alters signaling networks and protein levels. Thus, the goal of this project is to analyze cellular response to Tb-161 radioimmunotherapy by proteomics and phosphoproteomics in our T-cell lymphoma mouse model. We anticipate that our study will not only broaden our understanding of cancer radiobiology but also identify potential RIT-induced and survival-driving mechanisms and pathways, which targeting can be further explored for the development of novel radio-sensitizing strategies.