Wang Xiaoying, Yang Keqing, Yang Bin, Wang Rui, Zhu Yongliang, Pan Tianhui
Laboratory of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, People's Republic of China.
Internal Medicine, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, People's Republic of China.
Cancer Immunol Immunother. 2025 Feb 1;74(3):86. doi: 10.1007/s00262-024-03930-z.
Tumor-associated macrophages (TAMs) are among the most common types of immune cells in the colon cancer microenvironment. Reprogramming M2-type TAMs with immunosuppressive functions into M1-type TAMs with proinflammatory functions is a novel strategy for reshaping the tumor microenvironment (TME) and enhancing the efficacy of immunotherapy in colon cancer. However, the key molecules and mechanisms underlying TAM polarization require further clarification. Our previous study suggested that ANKRD22 may play a role in regulating the functional state transition of macrophages. However, the expression levels of ANKRD22 in colon TAMs and its specific effects on tumor proliferation remain unclear. In the present study, we observed elevated ANKRD22 expression in M1-type TAMs. The expression level of ANKRD22 was positively correlated with the survival period of patients with colon cancer and with the infiltration abundance of M1-type TAMs, and ANKRD22 expression was negatively correlated with the infiltration abundance of M2-type TAMs. A significant decrease in ANKRD22 expression in macrophages cocultured with colon cancer cell culture supernatant as well as in macrophages directly derived from colorectal cancer tissues was observed. Single-cell RNA sequencing, spatial transcriptomic studies, and subcutaneous xenograft experiments in mice revealed that Ankrd22 silencing altered the subtype distribution of macrophages, attenuated their proinflammatory activity, and enhanced their protumor activity. Additionally, we identified a small-molecule ANKRD22 upregulator that could aid in the development of novel therapeutics targeting TAM remodeling.
肿瘤相关巨噬细胞（TAMs）是结肠癌微环境中最常见的免疫细胞类型之一。将具有免疫抑制功能的M2型TAMs重编程为具有促炎功能的M1型TAMs是重塑肿瘤微环境（TME）和提高结肠癌免疫治疗疗效的一种新策略。然而，TAM极化的关键分子和机制仍需进一步阐明。我们之前的研究表明，ANKRD22可能在调节巨噬细胞功能状态转变中发挥作用。然而，ANKRD22在结肠TAMs中的表达水平及其对肿瘤增殖的具体影响仍不清楚。在本研究中，我们观察到ANKRD22在M1型TAMs中表达升高。ANKRD22的表达水平与结肠癌患者的生存期以及M1型TAMs的浸润丰度呈正相关，而ANKRD22的表达与M2型TAMs的浸润丰度呈负相关。观察到与结肠癌细胞培养上清液共培养的巨噬细胞以及直接来源于结直肠癌组织的巨噬细胞中ANKRD22表达显著降低。单细胞RNA测序、空间转录组学研究以及小鼠皮下异种移植实验表明，Ankrd22沉默改变了巨噬细胞的亚型分布，减弱了它们的促炎活性，并增强了它们的促肿瘤活性。此外，我们鉴定出一种小分子ANKRD22上调剂，其有助于开发针对TAM重塑的新型疗法。
