The propensity of cancer cells to escape the immune system and to initiate a complex balance environment is due to its ability to utilize immune cells via associated factors, including non-tumoral components such as blood vessels, fibroblasts, cells, and signaling molecules. Collectively, these are referred to as the tumor microenvironment (TME). TME is the tumor's surrounding environment and has a crucial role in promoting tumor progression, angiogenesis, metastasis, and increasing tumor resistance to several therapies. TME’s immunosuppressive factors depress the immune response after altering the metabolism of immune cells within TME. Accordingly, targeting TME with nanoparticles may be a beneficial tool to regulate and enhance the efficacy of tumor immunotherapies. Here, we review distinct structural and functional properties of immune cells within TME, tumor-associated immunosuppressive factors, and the interaction between TME and immune cells. We finish with a summary of recent findings related to novel nanoparticle strategies to target TME.