The TMBIM1-YBX1 axis orchestrates MDSC recruitment and immunosuppressive microenvironment in pancreatic cancer

<b>Background:</b> Pancreatic ductal adenocarcinoma (PDAC) is notorious for its profoundly immunosuppressive nature. The complex crosstalk between diverse immune cell types and heterogeneous tumor cell populations shapes this challenging tumor immune microenvironment (TIME). In this study, the role of transmembrane BAX inhibitor motif-containing 1 (TMBIM1) in modulating the TIME and its potential as a therapeutic target in PDAC were investigated. <b>Methods:</b> RNA sequencing was used to assess differential gene expression between PANC-1 cells with TMBIM1 knockdown and control cells. Single-cell RNA sequencing further validated the role of TMBIM1 in modulating the expression of CCL2 and PD-L1. Mechanistic insights were gained through chromatin immunoprecipitation, ELISA, real-time quantitative PCR, and flow cytometry experiments. To evaluate the impact of TMBIM1 on immune cell dynamics, we employed an <i>in vitro</i> chemotaxis assay and an <i>in vivo</i> C57BL/6J mouse xenograft model to examine CD8⁺ T-cell activation and myeloid-derived suppressor cell (MDSC) infiltration. Additionally, the therapeutic potential of TMBIM1 knockdown combined with anti-PD-1 antibody treatment was investigated in PDAC animal models. <b>Results:</b> TMBIM1 was significantly upregulated in pancreatic cancer tissues and cell lines, driving pancreatic cancer cell proliferation, growth, and migration both <i>in vitro</i> and <i>in vivo</i>. Elevated TMBIM1 expression induced high infiltration of MDSCs and fostered an immunosuppressive tumor microenvironment. Mechanistically, TMBIM1 binds to the transcription factor Y box binding protein 1 (YBX1), which in turn increases the affinity of YBX1 for the PD-L1 and CCL2 gene promoters. This interaction results in their upregulation, leading to increased MDSC infiltration, thereby facilitating the immunosuppressive TIME in PDAC. Notably, the combination of TMBIM1 knockdown with anti-PD-1 therapy had a more potent antitumor effect than anti-PD-1 therapy alone. <b>Conclusions:</b> Our study reveals that the TMBIM1/YBX1 axis is a key driver of immune evasion in PDAC and shapes the immunosuppressive TIME through the upregulation of CCL2 and PD-L1 expression. These findings highlight TMBIM1 as a potential therapeutic target to sensitize PDAC to immunotherapy.