ANKRD22 Participates in Pro-inflammatory Activities of Macrophages in the Tumor Microenvironment of Colon Cancer

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 pro-inflammatory 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 current study, we observed elevated ANKRD22 expression in M1-type TAMs. The expression level of ANKRD22 correlated positively with the survival period of patients with colon cancer, as well as with the infiltration abundance of M1-type TAMs and negatively with the infiltration abundance of M2-type TAMs. A significant decrease in ANKRD22 expression in macrophages co-cultured with colon cancer cell culture supernatant as well as in macrophages directly derived from colorectal cancer tissues were observed. Single-cell RNA sequencing, spatial transcriptomic studies, and subcutaneous xenograft experiments in mice showed that silencing of Ankrd22 altered the subtype distribution of macrophages, attenuated their pro-inflammatory activity, and enhanced their pro-tumor activity. Finally, we identified a potential ANKRD22 agonistic small-molecule lead compound that could contribute to the development of novel therapeutics based on TAM remodeling.