Table 2.

Combinations of FGFRi + ICI: rationale and its applications.

Category	Rationale for Treatment Synergism between FGFRi and ICI in a/m UBC
Tumor infiltrating NK/NKT/cytotoxic CD8+ T cells	Immune effector cells involved in cancer cell elimination
Tumor infiltrating dendritic cells/MDSCs/M2-TAMs/Treg	Defective immune modifiers contributing to tumor immune evasion
MDSCs	Directly interact with tumor cells and promote cancer cell stemness Lead to immune evasion in the TME by activating M2-TAMs/Treg cells and inhibiting NK/cytotoxic CD8+ T cells
M2-TAMs	Express immunosuppressive paracrine factors, such as IL-10, TGFβ, and ARG1
Endothelial progenitor cell-like MDSCs/M2-TAM subset	Promote tumor angiogenesis
Dendritic cell-specific C-type lectin TAMs	Contribute increased levels of Treg cells/cytotoxic CD8+ T cells with an impaired cytolytic activity (reduced levels of the cytotoxins perforin, granzyme B, and IFN-γ)
Treg cells	Suppress antitumor immune activity through release of inhibitory cytokines (TGFβ, IL-10) and cell–cell contact via immune checkpoint molecules (CTLA-4, LAG3) Induce apoptosis of cytotoxic CD8+ T cells through cytolysis via perforin or granzyme, IL-2 consumption and ATP deprivation through CD38 hydrolyzing ATP to ADP and AMP
Immune exclusion phenotype caused by FGFR 3 mutations	Caused by the sequestration of cytotoxic CD8+ T cells in TME due to increased deposition of fibronectin and collagen in the extracellular matrix
ICIs	Target negative regulating cell receptors on immune cells, predominantly T cells, leading to reactivation of those cells and promotion of a durable antitumor response Seem to be less effective on UBC TCGA luminal I subtype with attenuated CD8+ cytolytic activity, lower expression of PD-L1 in both tumor cells and immune cells
FGFRis	Reverse the TME from immunologically cold tumors into hot tumors by enhancing T cell recruitment by normalizing tumor blood vessels Target immune suppressive cells in TME such as MDSCs/M2-TAMs/CAFs in direct or indirect manners