众所周知，结直肠癌（CRC）对免疫疗法具有抵抗力。在我们的 I 期临床试验中，一名患者在溶瘤病毒疗法和免疫疗法联合治疗期间实现了 313 天的长期缓解。为了更深入地了解潜在的分子机制，我们对这名患者和三名无反应者进行了全面的多组学分析。我们的研究表明，最初，与无应答者相比，该应答者的肿瘤微环境 (TME) 呈现出最小的 T 细胞和自然杀伤细胞浸润，以及相对较高的巨噬细胞存在。值得注意的是，在治疗期间，应答者肿瘤组织中的 CD4 T 细胞、CD8 T 细胞和 B 细胞逐渐增加。与此同时，与 T 细胞激活和细胞毒性相关的转录因子（包括 GATA3、EOMES 和 RUNX3）显着上调。此外，对应答者外周血样本的动态监测显示，循环肿瘤 DNA (ctDNA) 迅速减少，表明其作为治疗效果的早期血液生物标志物的潜力。总的来说，我们的研究结果证明了联合溶瘤病毒疗法和免疫疗法对某些 CRC 患者的有效性，并提供了分子证据，表明病毒疗法有可能将“冷”TME 转变为“热”TME，从而提高对免疫疗法的敏感性。© 2024。作者（ s）。

Colorectal cancer (CRC) is known to be resistant to immunotherapy. In our phase-I clinical trial, one patient achieved a 313-day prolonged response during the combined treatment of oncolytic virotherapy and immunotherapy. To gain a deeper understanding of the potential molecular mechanisms, we performed a comprehensive multi-omics analysis on this patient and three non-responders. Our investigation unveiled that, initially, the tumor microenvironment (TME) of this responder presented minimal infiltration of T cells and natural killer cells, along with a relatively higher presence of macrophages compared to non-responders. Remarkably, during treatment, there was a progressive increase in CD4+ T cells, CD8+ T cells, and B cells in the responder's tumor tissue. This was accompanied by a significant upregulation of transcription factors associated with T-cell activation and cytotoxicity, including GATA3, EOMES, and RUNX3. Furthermore, dynamic monitoring of peripheral blood samples from the responder revealed a rapid decrease in circulating tumor DNA (ctDNA), suggesting its potential as an early blood biomarker of treatment efficacy. Collectively, our findings demonstrate the effectiveness of combined oncolytic virotherapy and immunotherapy in certain CRC patients and provide molecular evidence that virotherapy can potentially transform a "cold" TME into a "hot" one, thereby improving sensitivity to immunotherapy.© 2024. The Author(s).