Onconutraceuticals: How "Mediterranean" Biocomponents Can Reduce Inflammation and Break Tumor Resistance

Nutrients has published a review by researchers from the University of Magna Grecia (Catanzaro) that looks at cancer prevention and treatment support through the lens of nutrition and nutraceuticals. The authors examine the mechanisms by which components of the Mediterranean diet – from bergamot polyphenols to olive oleuropein and resveratrol – interfere with oxidative stress, inflammation, the tumor microenvironment, and the cell cycle. The main idea is simple but important: many natural molecules act “dualistically” – they protect healthy tissue as antioxidants, but in tumor cells they trigger pro-oxidant and pro-apoptotic cascades, which theoretically helps both in prevention and as an adjuvant to chemotherapy.

Background

Cancer remains one of the leading causes of premature death worldwide, with IARC estimating nearly 20 million new cases and 9.7 million deaths in 2022, and the number of diagnoses could rise to 35 million by 2050. With the population aging and the proportion of risk factors (smoking, alcohol, obesity) increasing, there is growing interest in simple, scalable strategies for prevention and supportive care, primarily nutrition and nutraceuticals.

The Mediterranean dietary pattern—a “core” of vegetables and fruits, whole grains, legumes, nuts, fish, and extra virgin olive oil as the primary fat—is consistently associated with lower systemic inflammation. In meta-analyses of RCTs and prospective studies, this pattern was the most likely to reduce CRP and IL-6 (albeit with high heterogeneity), which is biologically consistent with the idea of “cooling” the inflammatory microenvironment important for carcinogenesis and tumor progression.

This gave birth to the field concept of onconutraceuticals - natural bioactives of food (polyphenols, flavonoids, terpenoids, etc.), which can work dually: in normal tissues - as antioxidants/anti-inflammatory agents; in tumor cells - as "prooxidants" that bring stress to apoptosis and interfere with the survival of malignant cells. For olive components - hydroxytyrosol and oleuropein - reviews show modulation of NF-κB/STAT3 pathways, influence on cytokine expression (TNF-α, IL-6) and cell cycle signals, which makes them candidates for adjuvants to standard therapy.

At the same time, “transferring from a test tube to a ward” runs into several bottlenecks: bioavailability (many polyphenols are poorly absorbed and quickly metabolized), variability of composition (depends on the variety, technology and storage), and also the risk of drug interactions and the need to test synergy with specific chemotherapy regimens in rigorous RCTs. Therefore, current reviews emphasize: there are prospects - from reducing toxicity to enhancing tumor response - but the evidence base should shift from preclinical to well-planned clinical studies with control of forms, doses and combination regimens.

Against this backdrop, a new review in Nutrients focuses the lens: not on “diet in general,” but on specific biocomponents of the Mediterranean pattern, their targets (inflammation, oxidative stress, tumor microenvironment, cell cycle) and application scenarios – from prevention to adjuvant support for cancer treatment. This is a logical continuation of the trend towards precision nutrition, where not only calories and macrodistribution are valuable, but also the molecular effects of individual nutrients in conjunction with therapy.

What exactly did the review show?

• This is a pathophysiological review: summarizing clinical and preclinical data on the Mediterranean diet (MedDiet) and key nutraceuticals (polyphenols, flavonoids, terpenoids) in the context of cancer prevention and support. Focus on how these substances modulate oxidative stress, inflammation, tumor microenvironment, cell cycle, and drug resistance.
• The authors' shortlist includes bergamot polyphenol fraction (BPF), cynaropicrin (Cynara cardunculus), oleuropein (olive), quercetin, resveratrol, and even serotonin as a dietary mediator. According to the studies, many of them act as antioxidants in healthy cells, while inducing "stress to apoptosis" in cancer cells.
• A separate topic is synergy with chemotherapy: natural components are capable of increasing tumor response and reducing toxicity (cardio-/hepato-), as well as interfering with the mechanisms of drug resistance. This is called "onconutraceuticals" - the integration of nutraceuticals into oncostrategies.

The Mediterranean diet in this puzzle is not just a “background,” but a lifestyle model: lots of vegetables, fruits, legumes, whole grains and nuts, extra virgin olive oil as the main fat, fish regularly, red wine in moderation. According to population and clinical studies, this pattern is associated with a lower risk of a number of tumors, better metabolism and a “healthier” microbiome, which indirectly affects carcinogenesis and treatment tolerance.

Key molecules and where they “hit”

• BPF (bergamot): reduces intracellular ROS/MDA, increases the activity of its own antioxidant enzymes (SOD/GPx); through ROS control affects NF-κB, HIF-1α and angiogenesis (VEGF). In theory, this simultaneously protects normal tissues and makes tumors vulnerable (pro-oxidant in cancer cells → apoptosis).
• Cynaropicrin (artichoke/thistle): a member of the sesquiterpene lactones, reviewed as a modifier of inflammatory pathways and cell cycle, making it a candidate for chemotherapy adjuvant.
• Oleuropein (olive/EVOO): typical MedDiet “glue” component: antioxidant and anti-inflammatory effects, influence on NF-κB/STAT axis; data support reduction of “background” inflammation and tissue protection.
• Quercetin/resveratrol: broad-spectrum polyphenols; roles in regulation of drug resistance (DNA repair, efflux, targets) and proapoptotics, as well as potential for synergy with cytostatics are discussed.
• Serotonin: considered a signaling molecule capable of altering the tumor microenvironment and interacting with the cell cycle; clinical relevance remains to be determined.

Why is “duality” not a minus, but a plus? Because the threshold/dose and context decide which way the effect will turn. Low and moderate oxidative stress activates NF-κB and cytokines (IL-6, TNF-α), and too high one breaks DNA and pushes the cell into apoptosis: through the mitochondrial pathway (cytochrome c → APAF1 → caspases) and external death receptors (Fas/TNF-R/TRAIL). On this “edge”, many nutraceuticals can actually protect normal cells from the toxicity of therapy, but push tumor cells to death.

Where exactly do they interfere?

• Oxidative stress and DNA: ROS drive HIF-1α/VEGF, EMT and metastasis; excess ROS produces 8-oxo-dG, double strand breaks and epigenetic disorders (DNMT/HDAC).
• Inflammation and NF-κB/STAT3: Nutraceuticals can suppress NF-κB, which simultaneously reduces IL-6/TNF-α and disrupts chemo-resistance pathways.
• Cell cycle/apoptosis: caspase activation, MOMP, Bcl-2/Bcl-XL imbalance; plus “metal chelation”, telomeric effects and even effects on drug-processing enzymes.

It is important to understand the scale of the task. Oncology is faced not only with increasing incidence (about 20 million new cases and 9.7 million deaths per year, according to IARC estimates), but also with resistance to therapy and side effects of chemoradiation. Hence the interest in “soft” adjuvants that can increase the effectiveness of standard regimens, reduce toxicity, and restructure the tumor microenvironment.

What the authors consider promising (and what is still missing)

• Clinical yes, but with engineering: many natural molecules have weak points in bioavailability and pharmacokinetics. We need formulations/nanocarriers, target dosing and long-term safety.
• Focus on synergy: design studies to see additive/superadditive effects with specific chemotherapy regimens, rather than testing the nutraceutical “by itself.”
• Moving from “diet in general” to targets: MedDiet remains the baseline, but adjuvants need response biomarkers, tumor phenotype stratification, and mechanistic endpoints.

And yet, this is still a review, not a guide to self-treatment. The authors emphasize: for "onconutraceuticals" to turn from a concept into a tool, strict RCTs with control of doses, forms and combination regimens are needed, as well as realistic goals - reducing toxicity, improving tolerability and quality of life, possible enhancement of response, and not replacing oncotherapy.

What does this mean for the reader (cautious practical conclusions)

• The Mediterranean eating pattern is a smart foundation at any stage: it is associated with lower "background" inflammation and better metabolism, and EVOO, vegetables/fruits, legumes and fish provide a natural "cocktail" of bio-components.
• No supplements "on the sly". Discuss any nutraceuticals with an oncologist during active treatment: even "natural" substances interact with cytostatics and hepatic drug metabolism.

Summary

The work neatly outlines the field of onconutraceuticals - from MedDiet as a "background" to specific molecules with plausible mechanisms and a chance for synergy with chemotherapy. Clinical recommendations are still far away, but the direction is clear: less inflammation and "fuel" for the tumor, more attacks on its vulnerabilities - and all this at the intersection of nutrition, pharmacology and oncology.

Source: Altomare C. et al. The Potential of Nutraceutical Supplementation in Counteracting Cancer Development and Progression: A Pathophysiological Perspective. Nutrients 17(14):2354, July 18, 2025. Open access. https://doi.org/10.3390/nu17142354