High expression of integral membrane protein 2A (ITM2A) was reported to be associated with favorable prognosis in several solid tumors including breast cancer. This study aimed to investigate the role of ITM2A in breast cancer, especially in respect to tumor microenvironment.ITM2A expression was evaluated based on qRT-PCR results on breast cancer specimens, as well as TCGA and GEO datasets. The influence of ITM2A expression on breast cancer cell proliferation and tumor growth were evaluated by CCK-8 assay, clonogenic assay, and murine xenograft models. Transwell assay was performed to observe the changes of invasion and migration capacity in breast cancer cells. To determine the biological functions of ITM2A, differentially expressed genes (DEGs) were screened based on RNA-sequencing data of MCF-7 cells overexpressed ITM2A. Then, functional annotation on DEGs was given by Gene Ontology and KEGG analysis. The stimulation on programmed cell death ligand 1 (PD-L1) expression when ITM2A overexpressed was determined by flow cytometry. Meanwhile, the correlation on expression levels between PD-L1 and ITM2A was tested via qRT-PCR on 24 breast cancer tissues, as well as public database.We demonstrated that ITM2A was frequently downregulated in breast cancer. Patients with high expression levels of ITM2A had longer overall survival and relapse free survival. Overexpression of ITM2A inhibited proliferation and impaired cells capacity of invasion and migration in vitro and in vivo. The DEGs in breast cancer cells overexpressed ITM2A were found to be associated with immunity responses. Moreover, ITM2A was found to facilitate breast cancer cells to express PD-L1. The correlation between PD-L1 and ITM2A was verified with both qRT-PCR assay and public database. Additionally, it was found that breast cancer had higher ITM2A expression frequently had more tumor-infiltrating lymphocytes (TILs).In summary, we found that high expression of ITM2A reduced the aggressivity of breast cancer cells and had a favorable effect on outcomes of patients with breast cancer. Moreover, ITM2A induced PD-L1 expression in breast cancer cells was accompanied with higher TILs numbers in tumor microenvironment.Copyright © 2021 Zhang, Xu, Xia, Wang, Li and Chen.