Fig. 4

Immunosuppressive tumor microenvironment contributing to acquired resistance to ICI therapy. Immune cells infiltrate into the TME, interacting with each other and tumor cells, harbor an immunosuppressive phenotype responsible for immune escape of tumor cells and the following acquired resistance during or after ICI treatment. These immunosuppressive cells include Tregs, TAMs, MDSCs, which express the alternate inhibitory immune checkpoints like TIM-3, LAG-3, BTLA, VISTA, and TIGIT, secrete cytokines and growth factors like IL-35, IL-10, and TGF-β, VEGF, or product IDO and adenosine, which negatively regulate anti-tumor immune immunity, remodel the extracellular matrix, and promote angiogenesis. As a result, the immunosuppressive TME promotes the tumor cell resistance to ICI therapy