囊蛋白C（CyC）是一种分泌型半胱氨酸蛋白酶抑制剂，其生物学功能尚不清楚。许多患者在糖皮质激素（GC）治疗期间，特别是在血浆中CyC水平升高。本研究利用基因组关联和结构方程模型将GC与CyC的系统调控联系起来，以确定CyC生产遗传学在英国生物库中的相关性。CyC的生产以及捕捉CyC生产易感性的多基因得分（PGS）与总体和癌症相关死亡的增加有关。我们发现GC受体直接靶向CyC，导致巨噬细胞和癌细胞对GC的响应性CyC分泌。CyC敲除的肿瘤显示显著降低的生长速度和TREM2+巨噬细胞的招募，后者与癌症免疫治疗失败有关。此外，由联合临床试验队列中的685名转移性癌症患者所构建的CyC生产PGS预测了检查点免疫治疗失败。综上所述，CyC可能通过TREM2+巨噬细胞招募起到GC效应通路的作用，并可能成为联合癌症免疫治疗的潜在靶点。©2023。

Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC's systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.© 2023.