Abstract：
This study delves into the unexplored realm of castration-resistant prostate cancer (CRPC) by investigating the role of TRIM28 and its intricate molecular mechanisms using high-throughput single-cell transcriptome sequencing and advanced bioinformatics analysis. Our comprehensive examination unveiled dynamic TRIM28 expression changes, particularly in immune cells such as macrophages and CD8+ T cells within CRPC. Correlation analyses with TCGA data highlighted the connection between TRIM28 and immune checkpoint expression and emphasized its pivotal influence on the quantity and functionality of immune cells. Using TRIM28 knockout mouse models, we identified differentially expressed genes and enriched pathways, unraveling the potential regulatory involvement of TRIM28 in the cGAS-STING pathway. In vitro, experiments further illuminated that TRIM28 knockout in prostate cancer cells induced a notable anti-tumor immune effect by inhibiting M2 macrophage polarization and enhancing CD8+ T cell activity. This impactful discovery was validated in an in situ transplant tumor model, where TRIM28 knockout exhibited a deceleration in tumor growth, reduced proportions of M2 macrophages, and enhanced infiltration of CD8+ T cells. In summary, this study elucidates the hitherto unknown anti-tumor immune role of TRIM28 in CRPC and unravels its potential regulatory mechanism via the cGAS-STING signaling pathway. These findings provide novel insights into the immune landscape of CRPC, offering promising directions for developing innovative therapeutic strategies.
摘要：
这项研究通过使用高通量单细胞转录组测序和先进的生物信息学分析研究TRIM28的作用及其复杂的分子机制，深入研究了去势抵抗前列腺癌（CRPC）的未开发领域。我们的全面检查揭示了动态的TRIM28表达变化，特别是在CRPC内的免疫细胞如巨噬细胞和CD8+T细胞中。与TCGA数据的相关性分析强调了TRIM28与免疫检查点表达之间的联系，并强调了其对免疫细胞数量和功能的关键影响。使用TRIM28基因敲除小鼠模型，我们确定了差异表达的基因和富集的途径，揭示TRIM28在cGAS-STING途径中的潜在调控参与。体外，实验进一步说明，前列腺癌细胞中TRIM28基因敲除通过抑制M2巨噬细胞极化和增强CD8+T细胞活性而诱导了显著的抗肿瘤免疫作用。这一有影响力的发现在原位移植肿瘤模型中得到了验证，其中TRIM28基因敲除表现出肿瘤生长的减速，减少M2巨噬细胞的比例，增强CD8+T细胞的浸润。总之,这项研究阐明了迄今为止未知的TRIM28在CRPC中的抗肿瘤免疫作用，并通过cGAS-STING信号通路揭示了其潜在的调节机制。这些发现为CRPC的免疫前景提供了新的见解，为开发创新的治疗策略提供有希望的方向。
