Tumor-educated cells in tumor microenvironment: Key drivers of immunotherapy resistance

In the past decade, immunotherapies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death 1 (PD-1), and PD-1 ligand (PD-L1) have been approved for solid tumors. However, some patients demonstrate suboptimal clinical outcomes due to resistance. The tumor microenvironment (TME) significantly affects the efficiency of immunotherapy by mediating interactions between tumor and non-tumor cells, including dendritic cells, T cells, B cells, macrophages, neutrophils, NK cells, and myeloid-derived suppressor cells (MDSCs). These non-tumor cells often exhibit two phenotypes with altered functions, and tumor cells drives their transition towards tumor promotion through tumor-education. Tumor-educated cells (TECs) are cells influenced by tumor cells, which acquire immune-suppressive phenotypes and promote tumor progression through resistance to anti-cancer therapies. These cells undergo modifications in response to signals from the tumor, which can influence their roles in tumor progression. Their dynamic interactions with tumor cells contribute to the reshaping of the TME, facilitating cancer growth and immune modulation. This review summarizes research on TECs in TME, explores mechanisms related to tumor education, and discusses their role in tumor progression and immunotherapy resistance. Additionally, potential therapeutic approaches targeting these cells are also reviewed, which may complement current treatment strategies.