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. 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. •Anti-tumor immune balance in UBC possesses prognostic and therapeutic values.•Heterogenic factors enroll the UBC's immune microenvironment and impact the tumor's fate.•Heterogenic factors include chemokines and immune checkpoints.•Urinary bladder cancer cells have a paracrine effect on the tumor's immune microenvironment.