Cellular transdifferentiation: a determinant of cancer malignancy, therapy resistance, and microenvironment remodeling

Cellular transdifferentiation enables tumor cells to alter differentiated phenotypes, acquiring capabilities, such as invasiveness, stemness, or drug resistance, in response to microenvironmental stress and therapeutic pressure. This review synthesizes recent findings across solid tumors and hematologic malignancies, elucidating plasticity's pivotal role in carcinogenesis. We delineate the complex molecular networks driving these fate transitions, including the core epithelial plasticity axis (TGF-β/Snail/EZH2/HOTAIR) and the androgen receptor (AR) inhibition-induced neuroendocrine differentiation (NED) pathway prominent in castration-resistant prostate cancer (CRPC). Crucially, the acquisition of cancer stem cells (CSCs) and the activation of stromal cells, such as cancer-associated fibroblasts (CAFs) and mesenchymal stem cells (MSCs), are integral to cancer plasticity within the tumor microenvironment (TME). These cells then co-construct a pro-carcinogenic ecosystem via paracrine signaling and epigenetic reprogramming. Finally, we survey emerging therapeutic strategies targeting these plasticity drivers and associated cellular phenotypes, such as utilizing epigenetic modulators or transdifferentiated cell-based drug delivery systems, offering promising avenues to circumvent therapeutic resistance in advanced cancer.