The "serine code" of metabolic reprogramming: multidimensional roles of the serine synthesis pathway in tumors and novel breakthroughs for targeted therapy.

As a pivotal contributor to tumor metabolism following glucose and glutamine, serine plays a crucial role in the metabolic network of tumors via its de novo synthesis pathway (SSP). The SSP is aberrantly activated in a variety of malignant tumors and promotes tumor progression through multi-dimensional mechanisms. On the one hand, it provides the material basis and one-carbon units required for the synthesis of nucleotides, proteins and phospholipids to support the rapid proliferation of tumor cells. On the other hand, it maintains cellular redox homeostasis by generating glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH). Furthermore, it regulates the tumor immune microenvironment through metabolic reprogramming, inducing macrophage polarization and modulating T-cell function, thereby shaping an immunosuppressive microenvironment. The activity and stability of key enzymes in the SSP are precisely regulated by transcription factors (such as c-Myc, HIF-1α, and NRF2), epigenetic modifications (including m5C and m6A), and post-translational modifications (such as methylation, ubiquitination, and deacetylation). Meanwhile, the SSP forms an interactive network with tumor signaling pathways including Akt, mTOR, and EGF-ERK, collectively driving metabolic reprogramming. Therapeutic strategies targeting the SSP have emerged as a research hotspot, encompassing dietary intervention, the development of inhibitors targeting key enzymes such as phosphoglycerate dehydrogenase (PHGDH), as well as combination therapies with radiotherapy, chemotherapy and immunotherapy. Notably, these strategies have shown promising potential in reversing drug resistance to BRAF inhibitors, sorafenib, 5-fluorouracil (5-FU) and other agents, providing novel strategies for pan-cancer therapy. Through a systematic and comprehensive analysis of the multi-dimensional functions, heterogeneous regulation and roles in therapeutic resistance of the SSP across cancer types, this review aims to elucidate the conserved principles and cancer-specific characteristics of the SSP as a metabolic hub. Additionally, we discuss the prospects and unique challenges of precise intervention strategies targeting the SSP in overcoming tumor heterogeneity and drug resistance.