Beta-Arrestin 1 Deficiency Enhances Host Anti-Myeloma Immunity Through T Cell Activation and Checkpoint Modulation

<i>Beta-arrestin 1</i> (<i>ARRB1</i>) is a multifunctional adaptor protein that regulates diverse signaling pathways beyond its canonical role in G-protein-coupled receptor desensitization. While <i>ARRB1</i> has been implicated in cancer progression, its role in modulating host immunity against multiple myeloma (MM) remains unexplored. Here, we demonstrate that host <i>ARRB1</i> deficiency significantly enhances anti-myeloma immunity and prolongs survival in a syngeneic murine MM model. Using Vk*MYC myeloma cells transplanted into wild-type and <i>ARRB1</i> knockout mice, we show that <i>ARRB1</i> deficiency in the host microenvironment promotes robust T cell infiltration and activation while reducing immunosuppressive myeloid populations. Notably, <i>ARRB1</i> knockout mice exhibited markedly decreased programmed cell death protein-1 (<i>PD-1</i>) expression on both T cells and myeloid-derived suppressor cells, indicating reduced immune exhaustion. Furthermore, <i>ARRB1</i> deficiency conferred protection against myeloma-induced bone disease, suggesting a dual role in immune regulation and bone homeostasis. These findings establish ARRB1 as a critical negative regulator of host anti-myeloma immunity and identify it as a potential therapeutic target for enhancing immunotherapy efficacy in MM.