香港中文大学于军课题组的研究显示，肿瘤常驻益生菌丁酸梭菌通过抑制IL-6介导的免疫抑制提高aPD-1在结直肠癌模型中的疗效。这一研究成果发表在2025年8月7日出版的国际学术期刊《癌细胞》上。

研究人员发现丁酸梭菌是一种增强CRC抗PD-1功效的益生菌。在微卫星不稳定-高（MSI-H）和微卫星稳定（MSS） CRC原位移植中，丁酸梭菌增强了抗PD-1的抑瘤作用，这在AOM/DSS诱导的CRC和无菌小鼠中得到了验证。单细胞RNA-seq显示，丁酸梭菌激活细胞毒性CD8⁺ T淋巴细胞（CTLs）并损害肿瘤相关巨噬细胞（TAMs），特别是与抗PD-1联合使用。机制上，丁酸C. butyricum表面蛋白secD与CRC细胞受体葡萄糖调节蛋白78 （GRP78）结合，使GRP78和PI3K-AKT-NF-κB通路失活，导致白细胞介素(IL)-6分泌减少，IL -6是一种免疫抑制细胞因子，可钝化CTLs并诱导TAMs。在huCD34⁺人源化小鼠和自体CRC类器官-CTLs共培养系统中验证了丁酸梭菌增强抗PD-1功效的转化作用。综上所述，丁酸梭菌是一种很有前景的辅助ICB治疗。

据悉，大多数结直肠癌（CRC）患者对免疫检查点阻断（ICB）治疗没有反应。

附：英文原文

Title: Tumor-resident probiotic Clostridium butyricum improves aPD-1 efficacy in colorectal cancer models by inhibiting IL-6-mediated immunosuppression

Author: Mingxu Xie, Kai Yuan, Yongxin Zhang, Yating Zhang, Ruyi Zhang, Jiuhe Gao, Wenchao Wei, Lanping Jiang, Tianhui Li, Yanqiang Ding, Luyao Wang, Yufeng Lin, Chi Chun Wong, Jun Yu

Issue&Volume: 2025-08-07

Abstract: Most colorectal cancer (CRC) patients do not respond to immune checkpoint blockade (ICB) therapy. Here, we identify Clostridium butyricum as a probiotic that boosts anti-PD-1 efficacy in CRC. In orthotopic allografts of microsatellite instability-high (MSI-H) and microsatellite stable (MSS) CRC, C. butyricum potentiates tumor suppressive effect of anti-PD-1, which is verified in AOM/DSS-induced CRC and germ-free mice. Single-cell RNA-seq reveals that C. butyricum activates cytotoxic CD8+ T lymphocytes (CTLs) and impairs tumor-associated macrophages (TAMs), especially in conjunction with anti-PD-1. Mechanistically, C. butyricum surface protein secD binds to CRC cell receptor glucose-regulated protein 78 (GRP78), which inactivates GRP78 and PI3K-AKT-NF-κB pathway, leading to reduced secretion of interleukin (IL)-6, an immunosuppressive cytokine that blunts CTLs and induces TAMs. Translational impact of C. butyricum in boosting anti-PD-1 efficacy is validated in huCD34+ humanized mice and autologous patient-derived CRC organoids-CTLs co-culture system. To summarize, C. butyricum is a promising adjuvant to augment ICB therapy.

DOI: 10.1016/j.ccell.2025.07.012

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00318-6