<p>Treatment-induced neuroendocrine prostate cancer (NEPC) represents a lethal evolution of prostate adenocarcinoma under androgen receptor pathway inhibition, posing a significant clinical challenge. In a recent landmark study, Wang et al<i>.</i> introduced an innovative internal Z-score based approach to comprehensively characterize the transcription factor (TF) landscape in prostate cancer progression, uncovering distinct TF profiles associated with adenocarcinoma and NEPC lineages. Notably, the study proposes a three-phase model of NEPC transdifferentiation—comprising de-differentiation, dormancy, and re-differentiation—revealing dynamic shifts in TF expression that underpin lineage plasticity and therapeutic resistance. This commentary critically evaluates the methodological advancements, the functional significance of the identified TF signatures, and the broader implications of these findings for developing novel therapeutic strategies. By delineating the molecular events driving the transition from androgen receptor (AR)-dependent adenocarcinoma to treatment-resistant NEPC, this work underscores the potential of targeting early and dormant phases of transdifferentiation to improve patient outcomes.</p>