An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8⁺ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell–specific functions. C5aR1 targeting resulted in increased NF-κB–dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features.

中文翻译：

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通过靶向补体受体 C5aR1 改善免疫​​抑制微环境中的放疗

免疫抑制微环境会导致肿瘤 T 细胞浸润不良，并与结直肠癌患者总体生存率降低相关。如何改善这些肿瘤的治疗反应仍然是一个挑战。使用综合筛选方法来识别癌症特异性的脆弱性，我们将补体受体 C5aR1 确定为可药物靶点，当其受到抑制时，可以改善放射治疗，即使在表现出免疫抑制特征和 CD8 ⁺ T 细胞浸润不良的肿瘤中也是如此。虽然 C5aR1 以其在免疫区室中的作用而闻名，但我们发现 C5aR1 在恶性上皮细胞上也强烈表达，突出了潜在的肿瘤细胞特异性功能。C5aR1 靶向导致 NF-κB 依赖性细胞凋亡增加，特别是在肿瘤而非正常组织中，表明在恶性细胞中，C5aR1 主要调节细胞命运。总的来说，这些数据表明，补体基因表达增加是受辐射肿瘤引起的应激反应的一部分，并且靶向 C5aR1 可以改善放疗，即使在表现出免疫抑制特征的肿瘤中也是如此。