Oncofetal Reprogramming: A New Frontier in Cancer Therapy Resistance

Oncofetal reprogramming has recently emerged as a critical concept in translational cancer research, particu-larly for its role in driving therapeutic resistance across a variety of malignancies. This biological process refers to the pattern of gene expression that is restricted to embryogenesis, but becomes expressed again in a sub-population of cancer cells. These genes are typically suppressed after embryogenesis, and their aberrant re-expression in tumors endows cancer cells with stem-like properties and enhanced adaptability. The GOAL of this review is to: i) Comprehensively examine the multifaceted nature of oncofetal reprogramming, ii) Elucidate its underlying molecular mechanisms, including its regulators and effectors, and iii) Evaluate its consequences on therapeutic response in different cancer types. We comprehensively integrate the latest findings from col-orectal, breast, lung, liver, and other cancers to provide a detailed understanding of how oncofetal programs interfere with tumor response to treatment. Among the candidates, YAP1 and AP-1 have emerged as central transcriptional drivers of this reprogramming process, especially in colorectal and breast cancers. We also ex-plore the distinct expression patterns of oncofetal genes across different tumor types and how these patterns correlate with treatment outcomes and patient survival. Lastly, we propose a dual-targeting therapeutic strategy that simultaneously targets both cancer stem cells and oncofetal-reprogrammed populations as more effectively approach to overcome resistance and limit recurrence.