Colorectal cancer can be considered a severe public health problem [1]. The third most frequent cancer presents considerable mortality, motivated by a diagnosis often made at an advanced stage of the disease. On the other hand, whenever detected early, the probability of controlling the disease is high, with reasonable survival rates at five years [2]. Thus, combating it depends on effective screening programs, early diagnosis, and individualized therapies with continuous and effective monitoring. These are the only ways to reduce the incidence and improve the outcomes of treated cases regarding survival and quality of life, simultaneously reducing the economic burden.

Currently, control of this type of cancer is based on three aspects: screening, diagnosis, and treatment. In screening programs, fecal occult blood tests and colonoscopies (on a smaller scale) are still the most used methods starting from 50 years of age in asymptomatic individuals. However, implementing molecular tests that measure the immune system’s response to the attack of colorectal cancer in screening programs could prove to be an essential step to achieve. A colonoscopy beyond screening is the main weapon in prevention (a colonoscopy with polypectomy prevents patients with adenomatous polyps from developing colorectal cancer) and tumor diagnosis. When the diagnosis of invasive cancer is made, it is necessary to carry out correct staging to plan an individualized therapy that may include surgery, radiotherapy, and chemotherapy in different modalities. Monitoring the response to treatment, screening for recurrence, and selecting the ideal treatment are also essential aspects of managing this oncological entity.

Biomarkers are substances that can be measured in biological fluids or tissues and predict the incidence or outcome of disease [3]. A promising biomarker should fulfill five essential requirements: good specificity, good sensitivity, cost effectiveness, ease of implementation, and the ability to detect the disease at its early stages. While sensitivity refers to the ability of the biomarker to detect diseased patients, specificity relates to its capability to reject other pathologies or healthy individuals.

Colorectal cancer-specific biomarkers are still an area in development. Many biomarkers with different characteristics are currently being analyzed, which can be investigated in blood, urine, or tissue using various methods with different sensitivities, specificities, and clinical practice applicability. One example of these markers is the carcinoembryonic antigen (CEA) measured in blood, which is the most common tool used in the clinic for disease monitoring after resection surgery. Others include tumor biomarkers, such as Kirsten rat sarcoma virus (KRAS) and V-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations or microsatellite instability, which have implications for therapeutic selection [4]. In the case of predictive biomarkers for response to neoadjuvant treatment in Locally Advanced Rectal Cancer (LARC), most biomarkers so far have been imaging variables and genetic parameters, as well as DNA- and RNA-based (TYMS polymorphisms, cell-free DNA, expression studies, microRNAs) [5,6,7]. Some are expensive, require state-of-the-art technology and complex laboratory procedures, and are not fully applied to the clinic yet.

Within this scope, whether in a targeted or untargeted fashion, metabolomics seems to be a tool for developing new biomarkers in cancer. Metabolomics uses body fluids and techniques to study low molecular weight molecules, such as amino acids, lipids, carbohydrates, and intermediates of various metabolic pathways. Some are already established procedures for screening and diagnosing other diseases, such as metabolic disorders. Metabolomics further allows the study of pathways known to be deregulated in cancer cells, providing a more thorough picture of the patient’s metabolic state. Glycolysis, the TriCarboxylic Acid Cycle (TCA), and mitochondrial metabolism have gathered much attention concerning cancer metabolism’s peculiarities. Their vast replicative potential, their metabolic plasticity, and their choice of aerobic glycolysis and concomitant lactate production as a source of energy—the Warburg effect—have made cancer cells an interesting source of possible metabolites for screening [8].

Among the vast array of molecules that might play a primordial role in the pathogenesis of cancer, amino acids have been attracting substantial attention. They have not only their role as building blocks for the synthesis of proteins but also can be considered alternative fuels in cancer due to their involvement in biosynthetic pathways [9]. For instance, glutamine and branched-chain amino acids provide organic molecules to fuel the TCA cycle; glutamate, glycine, and cysteine are used for glutathione synthesis, an antioxidant molecule essential to counter the production of reactive oxygen species during cell proliferation. In the same way, polyamines resulting from arginine catabolism have been associated with cancer development for decades [10]. Proteins involved in amino acid metabolism have also been under cancer research. They include transmembrane solute carriers and amino acid transporters, such as L-type amino acid transporter 1 and alanine–serine–cysteine transporter 2, which are usually upregulated in colorectal cancer [11]. Even though there is substantial biochemical evidence for the relevance of amino acids in cancer, there is still a lack of clinical output focusing exclusively on their use as biomarkers for the diagnosis, prognosis, and monitoring of therapeutic response in CRC (Figure 1).