肿瘤细胞尿素循环异常重塑髓系细胞免疫抑制表型并诱导免疫检查点抑制剂原发耐药的机制研究（Aberrant Urea Cycle Remodels Myeloid Immunosuppressive Pheno-types and Induces Primary ICB Resistance in Solid Tumors）

Abstract：PD-1/PD-L1 immunotherapy is widely applied in solid tumors, yet prevalent primary resistance severely limits clinicalefficacy. Tumor metabolic reprogramming is a major driver of immune cold tumor formation and immunotherapy resistance, whilemost current studies focus on conventional metabolic pathways with high homogeneity. Tumor urea cycle abnormality causes am-monia and urea accumulation, but its function in myeloid immune remodeling and ICB primary resistance remains poorly defined. Inthis study, clinical samples, in vitro co-culture systems and humanized tumor models were used to explore the underlying mechanism.The results revealed that aberrant urea cycle activation accumulates nitrogen toxic metabolites, activates the STAT3/PPARγ axis,and further induces M2 macrophage polarization and MDSC expansion, forming an immunosuppressive tumor microenvironment.Targeted urea cycle inhibition alleviated myeloid-mediated immune suppression, restored CD8 + T cell cytotoxicity, and reversed pri-mary ICB resistance. In conclusion, urea cycle dysfunction drives solid tumor ICB primary resistance via STAT3/PPARγ-dependentmyeloid immunosuppressive remodeling, providing a novel metabolic target to improve tumor immunotherapy.