Cancer is a lethal disease, responsible for ~9.6 million deaths annually, thus rendering it the second leading cause of mortality globally (1). The most common cancer types include lung, breast, colorectal, prostate, skin (melanoma) and stomach cancer. The treatment approach to cancer is multifactorial, with chemotherapy, radiotherapy and surgery being the main methods of treatment (1). The immune system plays a major role in all aspects of cancer, including its origin, development, metastasis, therapy and prevention. Cancer cells and the immune system are in a constant crosstalk, wherein cancer cells undergo three phases: i) Elimination; ii) equilibrium; and iii) escape. In the elimination phase, immune cells, particularly innate immune cells, are in constant surveillance, eliminating cells that are abnormal. The elimination process induces cancer cells to undergo immune-editing or sculpting, causing an increase in the number of cells that have decreased immunogenicity and become resistant to the immune surveillance process; this part is the equilibrium phase. The cells that become resistant can escape the immune system and develop into advanced-stage cancer (2).

It is possible to identify subsets of vulnerable populations who are at high risk of either developing cancer or who have cancer, but require intervention for preventing cancer progression. These populations include:

i) Aged individuals with ‘inflammaging’. There is sufficient evidence regarding how age-related pathologies, including cancer, cardiovascular diseases and type 2 diabetes, have a common inflammatory background, involving the process termed as ‘inflammaging’. In inflammaging, there is a constant systemic proinflammatory state with increased levels of circulating ILs, including IL-6 and IL-1, as well as TNF-α and other inflammatory markers. A chronic antigen load caused by infections, cellular senescence, a dysregulated DNA damage response, altered gut microbiota, meta-inflammation and some microRNAs (miRNAs/miRs) that are associated with aging also influence the causative factors for cancer, simultaneously influencing and aiding inflammaging, thereby leading to cancer formation and progression (3). Along with increasing age, studies have revealed that there is an enhancement in the number of natural killer (NK) cell subpopulations, as well as a redistribution. The re-distribution is characterized by an increase of CD56^bright cell populations, which are more immature, and of CD56^dim mature cells, with intrinsic, reduced cytotoxic activity at single-cell level. Moreover, NK cells from elderly populations produce less IFN-γ upon IL-2 stimulation (4). This immunocompromising nature may also influence the elderly population in becoming prone to cancer development.

ii) Individuals with genetic risk variants, which are prone to cancer development either caused by the variants themselves or due to negative influences on the immune system (5). The association between genes and cancer is well known. For instance, the most commonly mutated gene in all cancer types is p53. Moreover, inherited mutations in the BRCA1 and BRCA2 genes are associated with hereditary breast and ovarian cancer syndromes (5). The study by Imai et al (6) examined immune system weakness and cancer development. Between 1986 and 1990, these authors assessed the natural cytotoxic activity of peripheral blood mononuclear cells using an isotope-release assay in 3,625 residents of a Japanese population who were mostly aged >40 years. These authors also conducted an 11-year follow-up survey for the cohort members, aiming to examine cancer incidence and mortality. The follow-up results indicated that medium and high cytotoxic activity of peripheral-blood lymphocytes was associated with reduced cancer risk, whereas low activity was associated with increased cancer risk (6).

iii) Individuals with lifestyle and metabolic disorders: For >70 years, the association diabetes and cancer has been hypothesized (7). Epidemiological data have demonstrated that patients with diabetes are at an increased risk of developing various types of cancer, with an increased mortality rate. Several pathways have been proposed for the association between diabetes and cancer, including: a) Hyperglycaemia leading to increased cancer risk via augmented oxidative stress and DNA damage; b) hyperinsulinemia, due to exogenous insulin or insulin analogues [this view has been challenged by a previously published study (7)]; and c) chronic microinflammation with cytokine dysregulation (7). Hyperglycaemia in diabetes generally favours malignant cell proliferation by providing energy to the cancer cells. Increased levels of chronic inflammatory markers, including IL-1β, IL-6 and TNF-α, have been observed in diabetic patients, which may indicate the activation of the immune response in the progression and development of cancer cells. The uncontrolled proinflammatory response environment in diabetes, which is caused by chronic accumulation of glycated biomolecules and advanced glycation end products, leads to a chronic inflammatory state induced by the activation of the transcription factor NF-кB and the generation of reactive oxygen species (ROS) in cells. These factors promote a tumour-favourable microenvironment and potentially trigger immune system overactivation, ultimately leading to cancer growth (8,9). With regards to metabolic syndromes, chronic inflammation and cancer, a chronic and stable background inflammation has been proposed, referred to as a ‘hypothalamic microinflammation’ (9). This is caused by the hypothalamus atypically undergoing proinflammatory signalling activation, occurring alongside increases in age and the development of metabolic syndrome. This hypothalamic microinflammation has also been reported to programmatically control whole-body aging. Since aging is also associated with a chronic inflammatory state, negatively associated with longevity but positively with neurodegenerative diseases, an association between the hypothalamus and a microinflammatory state leading to cancer has become increasingly evident (10).

iv) Individuals with immune system weaknesses due to a) aged individuals with inflammaging; b) individuals with genetic risk variants; and c) individuals with lifestyle and metabolic disorders.

v) Patients with cancer undergoing chemotherapy, radiotherapy or surgery, which lead to therapy-induced immune dysfunction (11–13). Chemotherapy or a chemo- and radiotherapy combination have been reported to significantly delay the immune recovery to pre-treatment baseline levels. Similarly, surgery leads to a window of opportunity that allows the residual cancer cells, including those that have undergone distant metastases, to gain a foothold in the absence of NK cell surveillance (12).

Since conventional therapies have an associated risk of therapy-induced immune dysfunction, it is important to identify an approach that is effective in the long term as an adjunct to the other interventions, which would help maintain the normal function of the immune system, thereby enhancing its immune surveillance and antitumour properties, and ultimately playing a potential role in cancer prevention.

According to the Centers for Disease Control and Prevention in the USA, a vaccine is a product that stimulates the immune system of an individual to produce immunity against a specific disease (14). Vaccines in cancer may be therapeutic or preventive. Preventive cancer vaccines include proteins, peptides, DNA or RNA that can elicit or boost pre-existing antitumour immunity, leading to cancer elimination and the production of long-term memory to prevent tumour recurrence (15). The purpose of a therapeutic cancer vaccine is to control the cancer burden. Such vaccines include autologous patient-derived immune cell vaccines, tumour antigen-expressing recombinant virus vaccines, peptide vaccines, DNA vaccines and heterologous whole-cell vaccines derived from established human tumour cell lines (16). The personalized dendritic cell vaccine sipuleucel-T (Provenge) and recombinant viral prostate cancer vaccine PSA-TRICOM (Prostvac-VF) are widely known vaccines in the pre-approval/authorized approval/late clinical trial stages (17). Vaccines are often administered with adjuvants, which help to improve poorly immunogenic vaccines (18). Different types of novel adjuvants have been identified and applied with cancer vaccines, which include inorganic nanoparticles, organic molecules and polymers (19). Pathogens stimulate a ‘danger sensing’ signal via pathogen-associated molecular patterns (PAMPs). Inorganic nanoparticle-based adjuvants function in a similar manner to PAMPs, thereby stimulating antitumour immunity. Organic molecule-based adjuvants include small molecule-based factors, such as modified PAMPs, and are novel ligands for pattern recognition receptors (PRRs). Agonists of the Toll-like receptor family, which are type I transmembrane proteins that regulate the innate and adaptive immune responses (19), and agonists of stimulator of IFN genes (20) are examples of organic adjuvants. Polymer-based adjuvants concurrently help in drug delivery and act as PAMPs for immune system activation. At present, alum (a mixture of diverse aluminium salts) has been the only approved adjuvant in humans and remains one of the most common adjuvants in human vaccines. In addition to aluminium salts, oil-in-water emulsions containing squalene (e.g., MF59 and AS03), in vitro-assembled influenza-virus-like particles (e.g., virosomes) and the liposome-based adjuvant system AS01, are other licensed adjuvants in human vaccines (21).

However, it remains unknown whether there is a nutrition-based supplementation that can act as a potential vaccine adjuvant to facilitate cancer treatment, which can be both preventive and therapeutic.

β-glucans, as a result of their high biocompatibility and tolerability and satisfactory safety profile, possess numerous beneficial properties, establishing them as promising adjuvant candidates (21–23). Dietary phytochemical carbohydrates have been considered as effective cancer-preventing and therapeutic adjuvants, which can be supplemented continuously for a longer time period (24). Among such phytochemicals, saponins and β-glucans are widely distributed in the plant kingdom, and in their purified extract form, represent two of the most potent immunological adjuvants when injected as a mixture with antigen, or immunomodulators when orally ingested (25).

β-glucans are naturally occurring polysaccharides that are constituents of the cell walls of yeast, fungi (including mushrooms), some bacteria, seaweed and cereals (oat and barley) (26). β-glucans are functional bioactive compounds possessing hypocholesterolaemic, hypoglycaemic, immunomodulatory, antitumor, antioxidant and anti-inflammatory activities. Moreover, their macromolecular structure and functionality vary, depending on the source (27). Yeast-derived 1,3-1,6 β-glucans have been reported to exert more prominent biological response modifier (BRM) effects compared with β-glucans from other sources, including oats or barley (28). An immunomodulator includes any molecule or substance capable of interacting with the immune system, resulting in the up- or downregulation of specific components of the immune response (29). Immunomodulators comprise of an array of synthetic, natural and recombinant molecules. Natural molecules, including those found in curcumin, thyme, bay leaf, resveratrol, ginseng, echinacea, aloe vera, astragalus, goldenseal, flavonoids and essential oils, have been studied for their immunomodulation properties as nutritional supplements. However, direct comparison studies of individual immunomodulators are limited. Vetvicka et al (26) indicated that, amongst >20,000 published studies, compared with other immunomodulators, glucan was the most prominent one.

Glucans are BRMs that exert significant effects on various components of the immune system. Glucans are recognized by PRRs present on the membranes of immune cells, such as macrophages, monocytes, dendritic cells and NK cells, with their key receptors being Dectin-1 and complement receptor 3 (CR3; CD11b/CD18). Additional receptors include Toll-2, lactosylceramides and the scavenger receptor family (26).

In terms of cancer immunity, β-glucans have been demonstrated to possess various functions, including: i) the increase of infection resistance (which is of particular importance in virus-associated cancer types); ii) exerting antitumour effects by activating the adaptive and innate arms of the immune system; iii) stimulating immune cells, including leukocytes, T helper (Th) and NK cells; and v) exerting anticoagulant effects (30). β-glucans activate early innate reactions by acting as PAMPs. Glucan-activated B cells have been revealed to secrete proinflammatory lymphokines, including IL-8, through the involvement of several molecules including Dectin-1 receptors, MAPK and NF-κB and activator protein-1 transcription factors. β-glucans have also been demonstrated to be potent cellular immunity activators. The effects of β-glucan against various types of infection have been demonstrated, such as for example Leishmania (L.) major, Leishmania donovani, Candida albicans, Toxoplasma gondii, Streptococcus suis, Plasmodium berghei, Staphylococcus aureus, Escherichia coli, Mesocestoides corti, Trypanosoma cruzi, Eimeria vermiformis and Bacillus anthracis (26).

The antitumour effects of β-glucans against a wide variety of tumour types (26). The mechanism of the antitumor activity induced by β-glucans is proposed to occur via the enhancement of the immune system against tumour cells, as well as by inhibiting tumour invasion and progression via a complex modulation of the apoptotic and angiogenic mechanisms. The antitumour mechanisms enhanced by β-glucans involve several pathways. For instance, β-glucans bind with specific receptors, such as Dectin-1, expressed on myeloid cells, converting them into antigen presenting cells. This binding also activates CD4⁺ and CD8⁺ T-cells, which are stimulated to produce the proinflammatory cytokine, TNF-α, the antitumor cytokine, IFN-γ, granzyme B and perforins, all of them cytotoxic against cancer cells (31). The tumoricidal effects are also induced by switching suppressive M2 macrophages into inflammatory M1 macrophages and, in turn, activating Th1-type T cells, thereby enabling cancer cell destruction via the secretion of proinflammatory cytokines through these T-cells. Interactions between β-glucan and polymorphonuclear cells induce the release of ROS in the microenvironment, ultimately leading to tumour cell death. β-glucans also activate NK cell cytotoxicity via the production and release of proinflammatory cytokines and via complement activation (31). β-glucans have been demonstrated to effectively modify the tumour microenvironment, resulting in significant reduction of primary tumour growth and distant metastases (31). β-glucans have a strong synergy with antibodies (Abs) that naturally occur in cancer (26).

Accumulating evidence has indicated that chronic inflammation may lead to cancer development. Underlying infection or inflammation have been linked to 25% of all cancer cases (41). Any unresolved inflammation on account of the failure in the precise control of the immune response can continue to disrupt the cellular microenvironment, leading to alterations in cancer-related genes and post-translational modifications in key cell signalling proteins involved in the cell cycle, DNA repair and apoptosis (41). The identification of mononuclear inflammatory cells in close association with areas of hyperplasia and cellular atypia has been demonstrated even at very early stages of tumour development, further supporting the concept that inflammation is a major driving force that contributes to tumour initiation and/or initial tumour progression. The upregulation of non-specific proinflammatory cytokines (IFN-γ, TNF, IL-1α/β or IL-6) by immune cells, such as macrophages, mast cells and neutrophils, has been shown to promote tumour development (41). The inflammatory processes elicited by cancer itself are likely to be involved in their progression. Inflammation is also the common mechanism of action for numerous cancer risk factors, including infection, obesity, tobacco smoking, alcohol consumption, exposure to microparticles, dysbiosis and chronic inflammatory diseases, including pancreatitis and colitis. The administration of certain anti-inflammatory drugs, including aspirin, has also been reported to significantly reduce cancer risk. Thus, preventing or reversing inflammation has been suggested as a promising approach to cancer control (42).

Chronic-microinflammation culminating in cancer likewise requires focusing on metabolic disorders, including diabetes and cancer development. Several pathways have been proposed for the association between diabetes and cancer, including: i) hyperglycaemia leading to increased cancer risk via augmented oxidative stress and DNA damage; and ii) hyperinsulinemia, involving chronic microinflammation with cytokine dysregulation, which both require further attention. The uncontrolled proinflammatory response environment in diabetes caused by the chronic accumulation of glycated biomolecules and advanced glycation end products creates a chronic inflammatory state, via the activation of the transcription factor NF-кB and ROS generation in cells. Thus, a tumour-favourable microenvironment is promoted and immune system overactivation is potentially triggered, thereby leading to cancer growth. Moreover, with regards to chronic inflammation and cancer, a state of chronic and stable background inflammation has been proposed, known as ‘hypothalamic microinflammation’ (10), which occurs when the hypothalamus atypically undergoes proinflammatory signalling activation, and is associated with age increase and the development of metabolic syndrome.

β-glucans, particularly those that are yeast-derived, aid in combatting chronic microinflammation, thereby contributing to a cancer-preventive response, alongside their metabolic balancing activities (43,44), further adding to their effects in cancer prevention. A previous study on a yeast-derived β-glucan identified its antioxidant activity via H₂O₂ scavenging, as well as its in vivo anti-inflammatory potential in terms of myeloperoxidase activity and malondialdehyde and nitric oxide level reduction (45). In another study, the regular intake of β-glucan was demonstrated to exert an anti-inflammatory effect, which occurred by acting on IL-6, a pleiotropic cytokine that plays a pivotal role in acute phase responses in the balancing of the pro- and anti-inflammatory pathways (46).

Several factors and pathogenic processes have been identified, that can predispose an individual to a high risk of developing cancer and/or enable the progression of cancer, including: i) Chronic and microinflammation caused by infections, aging or metabolic disorders, including diabetes; ii) genetic causes; and iii) immune system weakness, either due to cancer or cancer therapy. Therefore, the prevention of cancer in the general population and in patients undergoing surgical or chemotherapeutic treatments is practically feasible, only if a consistent and simple approach can be followed, as for example a nutritional supplement to combat the compromise of the immune system and chronic microinflammation. The current review presented evidence of a BRMG, with regards to its potential function as a β-glucan vaccine adjuvant approach for the treatment of cancer through immunoenhancement. This approach may aid in the treatment of cancer in specific immunocompromised populations, as it induces a wide variety of biological response modifications. For example, the BRMG application may balance metabolic parameters, including blood glucose and lipid levels, increase peripheral blood cell cytotoxicity against cancer and alleviate chemotherapy-induced side effects in animal models. Thus, the use of a β-glucan vaccine adjuvant approach was suggested for the treatment of cancer via immunoenhancement as a potential strategy for a long-term prophylaxis in immunocompromised individuals or genetically prone to cancer.