Abstract
Beta-arrestin 1 (ARRB1) is a multifunctional adaptor protein that regulates diverse signaling pathways beyond its canonical role in G-protein-coupled receptor desensitization. While ARRB1 has been implicated in cancer progression, its role in modulating host immunity against multiple myeloma (MM) remains unexplored. Here, we demonstrate that host ARRB1 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 ARRB1 knockout mice, we show that ARRB1 deficiency in the host microenvironment promotes robust T cell infiltration and activation while reducing immunosuppressive myeloid populations. Notably, ARRB1 knockout mice exhibited markedly decreased programmed cell death protein-1 (PD-1) expression on both T cells and myeloid-derived suppressor cells, indicating reduced immune exhaustion. Furthermore, ARRB1 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.