直肠癌是第二大导致癌症相关死亡的原因。新辅助疗法对直肠癌患者的治疗经常会导致对治疗有良好反应和反应较差的个体，需要改变生活方式的切除手术。目前仍不清楚是什么因素决定了这种反应者/非反应者的分界线。我们的主要目标是确定肿瘤微环境中的哪些因素推动了一部分直肠癌患者对放疗的反应。我们还试图区分可能表明对治疗有积极反应的生物标志物，并设计联合治疗以增强放疗的疗效。为了解决这个问题，我们开发了一个直肠癌的正位移植小鼠模型，这个模型经过短期放疗后重现了临床上观察到的双峰反应。我们利用强大的转录组学和蛋白质分析组合，鉴定了反应性肿瘤和非反应性肿瘤之间的差异。我们的小鼠模型重现了在人类疾病中观察到的局部肿瘤对放疗的反应（反应者），大多数肿瘤没有反应。我们发现，反应性肿瘤具有增加的因损伤而导致的细胞死亡，以及与肿瘤相关巨噬细胞、肿瘤相关成纤维细胞和CD8 + T细胞相关的独特免疫激活标志。这种标志取决于放射线诱导增加的I型干扰素（IFNs）。我们研究了一种针对cGAS/STING途径的治疗方法，并证明了放疗后的反应率得到了改善。这些结果表明，调节I型干扰素途径有潜力提高直肠癌的放射治疗效力。

Rectal cancer ranks as the second leading cause of cancer-related deaths. Neoadjuvant therapy for rectal cancer patients often results in individuals that respond well to therapy and those that respond poorly, requiring life-altering excision surgery. It is inadequately understood what dictates this responder/nonresponder divide. Our major aim is to identify what factors in the tumor microenvironment drive a fraction of rectal cancer patients to respond to radiotherapy. We also sought to distinguish potential biomarkers that would indicate a positive response to therapy and design combinatorial therapeutics to enhance radiotherapy efficacy. To address this, we developed an orthotopic murine model of rectal cancer treated with short course radiotherapy that recapitulates the bimodal response observed in the clinic. We utilized a robust combination of transcriptomics and protein analysis to identify differences between responding and nonresponding tumors. Our mouse model recapitulates human disease in which a fraction of tumors respond to radiotherapy (responders) while the majority are nonresponsive. We determined that responding tumors had increased damage-induced cell death, and a unique immune-activation signature associated with tumor-associated macrophages, cancer-associated fibroblasts, and CD8 + T cells. This signature was dependent on radiation-induced increases of Type I interferons (IFNs). We investigated a therapeutic approach targeting the cGAS/STING pathway and demonstrated improved response rate following radiotherapy. These results suggest that modulating the Type I IFN pathway has the potential to improve radiation therapy efficacy in RC.