Transcriptional reprogramming of the tumor microenvironment by the YAP-TEAD4-PURB complex drives immunotherapy resistance in triple-negative breast cancer
Although immunotherapy has significantly advanced triple-negative breast cancer (TNBC) treatment, the majority of patients still experience poor clinical responses. By comparing RNA datasets from immunotherapy-sensitive and resistant patients, we identified purine-rich element-binding protein B (PURB) as a critical biomarker of immunotherapy failure and a key negative predictor of overall survival. Mechanistically, PURB formed a transcriptional complex with YAP1 and TEAD4 to co-activate the expression of colony-stimulating factor-2 (CSF2) and programmed death-ligand 1 (PD-L1). This dual-axis signaling reprogrammed the tumor microenvironment by utilizing CSF2 to alter tumor-associated macrophages (TAMs), which subsequently suppress CD4+ and CD8+ T-cell function, while simultaneously leveraging PD-L1 to facilitate direct immune evasion. Combining a CSF2-blocking antibody, or lipid nanoparticles loaded with siRNA targeted PURB, with anti-PD-1 therapy significantly enhanced immunotherapy efficacy in a preclinical breast cancer model. Our findings highlight the YAP1-TEAD4-PURB-CSF2 axis as a promising therapeutic target to counteract TNBC progression by restoring antitumor immune responses.