Extra Virgin Olive Oil: Molecular Mechanisms, Bioavailability Challenges, and Therapeutic Perspectives

Background/Objectives: Extra virgin olive oil (EVOO), a key component of the Mediterranean diet, has attracted research interest because olive-derived phenolics demonstrate potential anticancer activity in experimental models. This review summarizes evidence concerning whole EVOO, phenolic-enriched EVOO, olive phenolic extracts, and the isolated compounds hydroxytyrosol, oleuropein, oleocanthal, and oleacein. Methods: A structured narrative search of PubMed, Web of Science, ScienceDirect, and Google Scholar was conducted for literature published between 2015 and 2025. Evidence was reviewed for breast, prostate, colorectal, pancreatic, bone, oral, liver, gastric, hematological, and brain cancers. Comparatively limited evidence concerning cervical, endometrial, ovarian, melanoma, non-melanoma skin, and thyroid cancers was summarized separately. Results: The molecular evidence was derived primarily from cell culture and animal studies using isolated phenolics and concentrated extracts. Preclinical studies indicate that EVOO phenolics may demonstrate anticancer activity through multiple mechanisms, including antioxidant activity, anti-inflammatory effects, cell cycle arrest, induction of apoptosis, inhibition of metastasis, anti-angiogenic activity, and modulation of key signaling pathways, such as PI3K/AKT/mTOR, MAPK/ERK, NF-κB, JAK/STAT, Wnt/β-catenin, p53, and epithelial–mesenchymal transition-related pathways. Most molecular and pathway-level evidence was obtained using isolated phenolic compounds in cell culture or animal models, whereas evidence directly examining whole EVOO consumption was largely observational and substantially more limited. Experimental studies also reported that oleocanthal induced lysosomal membrane permeabilization, whereas hydroxytyrosol and oleuropein promoted mitochondria-mediated apoptosis. Furthermore, preclinical combination studies suggested enhanced tumor-cell sensitivity to selected chemotherapeutic, targeted, and immunotherapeutic agents. However, these effects have not been established in patients. Human evidence remains limited mainly to observational dietary associations and small exploratory interventions, with no conclusive demonstration of cancer prevention or therapeutic efficacy. Conclusions: Isolated EVOO-derived phenolic compounds demonstrated promising anticancer mechanisms in preclinical models. However, these results should not be directly extrapolated to dietary EVOO because experimentally administered doses, bioavailability, metabolism, and food-matrix interactions differ substantially from human dietary exposure. Therefore, well-designed studies using chemically characterized EVOO, pharmacokinetic investigations, and controlled human trials are required before dietary or clinical recommendations can be made.