Tumor-intrinsic execution of interferon-γ-associated immunity in bladder cancer: checkpoints in signaling, recruitment, and recognition.

Interferon-γ (IFN-γ) is a central mediator of antitumor immunity in bladder cancer, but an IFN-γ-rich tumor microenvironment does not necessarily translate into tumor control. Tissue-level inflammatory signatures capture overall immune activity and cannot determine whether malignant urothelial cells remain responsive to immune-derived IFN-γ or preserve the downstream functions required for immune elimination. This Mini Review examines tumor-intrinsic IFN-γ-associated immunity at three functional checkpoints: proximal IFN-γ sensing and signal transduction, chemokine-mediated effector-cell recruitment, and antigen-presentation-dependent tumor recognition. Bladder cancer models show that IFNGR-JAK-STAT1 responsiveness can be lost or attenuated, while separate tumor-intrinsic mechanisms can restrict CXCL9/CXCL10-dependent T-cell recruitment without a demonstrated proximal signaling defect. Antigen presentation forms a further checkpoint, with HLA-I and antigen-processing machinery altered through transcriptional, treatment-associated, and post-translational mechanisms. These mechanisms do not constitute a single linear IFN-γ resistance pathway. They instead mark distinct points at which inflammatory pressure can become uncoupled from tumor elimination. IFN-γ-responsive programs are also shaped by treatment context and signaling duration, as illustrated by CIITA/MHC-II biology and prolonged interferon signaling. Resolving these processes at malignant-cell, spatial, and longitudinal levels may improve the interpretation of BCG and checkpoint-blockade resistance and support more selective combination strategies.