A systematic review of omics discovery studies to identify pertinent metabolic pathways for locally advanced rectal cancer in response to neoadjuvant chemoradiotherapy.

Background: Locally advanced rectal cancer (LARC) has variable responses to neoadjuvant therapy (NAT). Therefore, identifying changes in biological pathways involved when LARC is treated with NAT is crucial for developing treatments to improve clinical outcomes, as NAT is both variable and unpredictable. Although individual studies have attempted to discern how the response differs at a transcriptomic, proteomic and metabolomic level, there has not been a unifying systematic review discerning the key changes in metabolic pathways in this patient population.

Aim of review: This systematic review aims to understand how metabolomics, proteomics and transcriptomics can demonstrate how the perturbed metabolic pathways of the NAT response in LARC can provide targets for further clinical research.

Key scientific concepts of review: Thirteen studies met the inclusion criteria, including seven metabolomic, five proteomic, and one transcriptomic study. Metabolomic analyses revealed consistent alterations in amino acid metabolism, the tricarboxylic acid (TCA) cycle, and glycerophospholipid metabolism. Proteomic findings supported these results, highlighting disruptions in glycolysis and gluconeogenesis. Joint pathway analysis demonstrated a strong correlation (r = 0.99, p < 0.0001) between metabolic changes observed across omics platforms. Key pathways such as alanine, branched-chain amino acid, and aspartate metabolism were commonly altered and may contribute to radio-resistance through enhanced energy production, reactive oxygen species (ROS) neutralization, and DNA repair mechanisms. The convergence of multi-omic data underscores the biological relevance of these metabolic reprogramming events. However, due to the limited availability of transcriptomic data meeting inclusion criteria, these findings are primarily driven by metabolomic and proteomic analyses, which constrains the extent of full multi-omic integration. Future studies should aim to validate these findings in clinical cohorts and explore how targeting these "survival" pathways could optimize treatment response in LARC.