TCF3 safeguards tumor-intrinsic interferon competence to restrain prostate cancer progression and immune escape

Prostate cancer commonly remains refractory to checkpoint blockade, consistent with an immune-cold microenvironment and tumor-intrinsic defects in interferon signaling. We report that loss of the basic helix-loop-helix transcription factor TCF3 defines a tumor-intrinsic mechanism that simultaneously drives aggressive progression and immune evasion. TCF3 expression is reduced in advanced and metastatic prostate cancer across multiple cohorts and in a Pten-driven model. In androgen-independent prostate cancer cells and organoids, TCF3 depletion enhances proliferation, clonogenicity, migration, and EMT-associated programs, while overexpression of TCF3 isoforms suppresses these malignant phenotypes. Transcriptomic profiling further shows that TCF3 loss profoundly downregulates interferon-α/γ response programs. Mechanistically, TCF3 promotes transcription of STAT2, preserving basal and inducible interferon signaling and downstream ISG expression; TCF3-deficient tumors exhibit reduced immune infiltration and impaired CD8⁺ T cell effector function in vivo. Notably, therapeutic innate immune activation partially restores interferon responses, and poly(I:C) plus PD-1 blockade reinvigorates cytotoxic T cell activity and markedly suppresses tumor growth. These data support TCF3 as a biomarker of interferon competence and a rational basis for selecting patients for innate agonist-checkpoint combinations.