Heterogeneity of modulatory immune microenvironment in bladder cancer

Urinary bladder cancer (UBC) is the ninth most common cancer worldwide. The intra-tumor heterogeneity of the UBC microenvironment explains the variances in response to therapy among patients. Tumor immune microenvironment (TIME) is based on the balance between anti-tumor and pro-tumorigenic immunity that eventually determines the tumor fate. This review addresses the recent insights of the cytokines, immune checkpoints, receptors, enzymes, proteins, RNAs, cancer stem cells (CSCs), tissue-resident cells, growth factors, epithelial-mesenchymal transition, microbiological cofactor, and paracrine action of cancer cells that mutually cross-talk within the TIME. In-depth balance and alteration of these factors influence the TIME and the overall tumor progression. This, in turn, highlights the prospects of the new era of manipulating these co-factors for improving the diagnosis, prognosis, and treatment of UBC. CONCLUSION: The heterogenic architecture of the TIME orchestrates the fate of the tumor. Nevertheless, recognizing the mutual cross-talk between these key players seems useful in prognostic and therapeutic approaches.