右侧和左侧结肠的肿瘤发生表现出不同的特征。我们旨在表征代表结肠肿瘤发生早期阶段的左侧和右侧腺瘤（AD）之间的差异。分析了单细胞和空间转录组数据集揭示右侧和左侧结肠 AD 之间的变化。使用细胞、动物实验和临床标本来验证结果。单细胞分析显示，在右侧AD中，杯状细胞显着减少，并且这些杯状细胞功能失调，粘蛋白生物合成减弱，抗原呈递缺陷。粘液屏障受损导致隐窝中形成生物膜，随后细菌侵入右侧 AD。空间转录组学揭示，被生物膜占据的隐窝周围的空间区域经历了脂多糖（LPS）的炎症反应和细胞凋亡过程。在右侧 AD 中发现了一个独特的 S100A11 上皮细胞群，其表达水平是由细菌 LPS 和肽聚糖诱导的。 S100A11 表达促进同基因免疫活性小鼠的肿瘤生长，其骨髓源性抑制细胞 (MDSC) 增加，但细胞毒性 CD8 T 细胞减少。使用耐受性良好的晚期糖基化终末产物 (RAGE) 受体拮抗剂（Azeliragon）靶向 S100A11，可显着损害肿瘤生长和 MDSC 浸润，从而提高抗程序性细胞死亡蛋白 1 疗法在结肠癌中的疗效。我们的研究结果表明，功能失调的杯状细胞和随之而来的细菌易位激活了右侧结肠 AD 中的 S100A11-RAGE 轴，该轴招募 MDSC 来促进免疫逃避。 Azeliragon 靶向该轴可提高结肠癌免疫疗法的疗效。© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Tumourigenesis in right-sided and left-sided colons demonstrated distinct features.We aimed to characterise the differences between the left-sided and right-sided adenomas (ADs) representing the early stage of colonic tumourigenesis.Single-cell and spatial transcriptomic datasets were analysed to reveal alterations between right-sided and left-sided colon ADs. Cells, animal experiments and clinical specimens were used to verify the results.Single-cell analysis revealed that in right-sided ADs, there was a significant reduction of goblet cells, and these goblet cells were dysfunctional with attenuated mucin biosynthesis and defective antigen presentation. An impairment of the mucus barrier led to biofilm formation in crypts and subsequent bacteria invasion into right-sided ADs. The regions spatially surrounding the crypts with biofilm occupation underwent an inflammatory response by lipopolysaccharide (LPS) and an apoptosis process, as revealed by spatial transcriptomics. A distinct S100A11+ epithelial cell population in the right-sided ADs was identified, and its expression level was induced by bacterial LPS and peptidoglycan. S100A11 expression facilitated tumour growth in syngeneic immunocompetent mice with increased myeloid-derived suppressor cells (MDSC) but reduced cytotoxic CD8+ T cells. Targeting S100A11 with well-tolerated antagonists of its receptor for advanced glycation end product (RAGE) (Azeliragon) significantly impaired tumour growth and MDSC infiltration, thereby boosting the efficacy of anti-programmed cell death protein 1 therapy in colon cancer.Our findings unravelled that dysfunctional goblet cells and consequential bacterial translocation activated the S100A11-RAGE axis in right-sided colon ADs, which recruits MDSCs to promote immune evasion. Targeting this axis by Azeliragon improves the efficacy of immunotherapy in colon cancer.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.