SOX11 is a pioneering transcription factor associated with conventional mantle cell lymphoma (MCL), an aggressive B‐cell malignancy with poor prognosis. However, its precise role in MCL remains unclear. Our preliminary data using a conditional SOX11 overexpression mouse model demonstrate that SOX11 induces MCL in mice. WP1 will assess SOX11’s impact on B-cell development via an integrated single-cell omics approach. We will characterize SOX11-driven transcriptional programs, chromatin accessibility, and B-cell receptor (BCR) biases during development, focusing on B1 and marginal zone B-cells (MZBs). WP2 tests the hypothesis that fetal-derived B1 cells, which display a self-antigen-biased BCR repertoire similar to MCL, serve as the disease’s cell-of-origin. We will conduct fetal liver transplant experiments, track clonal BCR dynamics during MCL initiation and progression, and determine whether transient SOX11 expression can reprogram mature B-cells into B1-like cells. WP3 focuses on novel therapeutic strategies by integrating drug repurposing and immune checkpoint therapy. Lead compounds identified from drug response profiling will be combined with BCL2 or BTK inhibitors and validated in MCL patient-derived xenografts. Using our immunocompetent SOX11/p53Mb1 mouse model, we will evaluate anti-PD-L1 therapy alone and in combination with targeted agents to overcome immune evasion linked to high PD-L1 expression in SOX11-induced MCL.