IRF1-driven chromatin and transcriptional regulation determines the anti-tumor responses to all-trans retinoic acid across cancer types.

All-trans retinoic acid (ATRA) is a potent differentiation inducer successfully used to treat acute promyelocytic leukemia (APL), with its therapeutic efficacy traditionally attributed to targeting the PML/RARα fusion oncoprotein. ATRA also exhibits anti-tumor activity in multiple non-APL malignancies. However, PML/RARα targeting alone does not fully explain the diverse ATRA-induced anti-tumor responses, and the early transcriptional regulators coordinating these responses remain incompletely understood. Here, we performed a time-series transcriptomic analysis in an ATRA-sensitive APL cell line and identified interferon regulatory factor 1 (IRF1) as a pivotal early regulator of ATRA response that orchestrates multiple downstream transcriptional programs. Mechanistically, chromatin immunoprecipitation sequencing (ChIP-seq) revealed that ATRA enhanced IRF1 chromatin occupancy and transcriptional activity, thereby activating gene networks linked to ATRA-induced myeloid differentiation, proliferation control, cell-cycle regulation, and the reformation of promyelocytic leukemia (PML) nuclear bodies. Further IRF1 knockdown markedly impaired these phenotypic effects, confirming its essential role in coordinating ATRA-induced cell fate transitions. Moreover, cross-cancer studies demonstrated that IRF1 activation and the associated IRF1-dependent transcriptional signatures were selectively enriched in ATRA-sensitive tumors but not in ATRA-resistant contexts. Leveraging this shared regulatory mechanism, we developed an IRF1_ATRA score that could predict tumor responsiveness to ATRA across hematopoietic and solid malignancies, thereby supporting the expansion of ATRA-based therapy to a broader range of cancers. Collectively, our findings indicate that IRF1-dependent chromatin and transcriptional regulation contribute to the diverse anti-tumor effects of ATRA and provide a framework for biomarker-guided evaluation of ATRA in cancer therapies.