The interactions and communications in tumor resistance to radiotherapy: Therapy perspectives

•Radiotherapy can change the balance between tumor suppressing and tumor promoting cells.•The release of some chemokines such as CXCL9 and cytokines like IFN-γ and TNF-α can boost anti-tumor immunity.•The release of IL-10 and TGF-β as well as upregulation of immune checkpoints is critical mechanisms for tumor regrowth.•Boosting tumor promoting signaling and suppression of immune checkpoints potentiate anti-tumor immunity. Tumor microenvironment (TME) includes a wide range of cell types including cancer cells, cells which are involved in stromal structure and immune cells (tumor suppressor and tumor promoting cells). These cells have several interactions with each other that are mainly regulated via the release of intercellular mediators. Radiotherapy can modulate these interactions via shifting secretions into inflammatory or anti-inflammatory responses. Radiotherapy also can trigger resistance of cancer (stem) cells via activation of stromal cells. The main mechanisms of tumor resistance to radiotherapy is the exhaustion of anti-tumor immunity via suppression of CD4+ T cells and apoptosis of cytotoxic CD8+ T lymphocytes (CTLs). Cancer-associated fibroblasts (CAFs), mesenchymal-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are the main suppressor of anti-tumor immunity via the release of several chemokines, cytokines and immune suppressors. In this review, we explain the main cellular and molecular interactions and secretions in TME following radiotherapy. Furthermore, the main signaling pathways and intercellular connections that can be targeted to improve therapeutic efficiency of radiotherapy will be discussed.