Cancer is a major challenge in the global public health field, and its morbidity and mortality rates continue to rise. According to the International Agency for Research on Cancer, ~20 million new cases of cancer alongside ~10 million cancer-related deaths were observed in 2022 and it has been predicted that there will be >35 million new cases by 2050 (1,2). It has been identified that family history, environment and lifestyle, and bacterial/viral infections are the main risk factors for cancer (1,3). Currently, natural product interventions such as lycopene and curcumin have become important strategies for cancer prevention and treatment, as most of these products are derived from vegetables, fruits and plants (4–7).

Lycopene, commonly referred to as ‘plant gold’, is a naturally occurring carotenoid mainly found in plants such as tomato, pink guava and watermelon, which provides them with a distinctive red color (Fig. 1) (8). Lycopene has been identified as an A-grade nutrient by the Food and Agriculture Organization, the Joint Expert Committee on Food Additives and the World Health Organization (9). The molecular formula of lycopene is C₄₀H₅₆, with 11 linear conjugated and 2 non-conjugated double bonds. This unique structure determines its strong antioxidant activity, such as quenching singlet oxygen, scavenging free radicals and inhibiting lipid peroxidation, which are associated with its notable health-promoting function (9,10). Moreover, these double bonds are sensitive to light, temperature and chemical reactions, which makes lycopene prone to isomerization (11). Notably, the bioavailability of cis-isomer is markedly higher compared with that of trans-isomer (12,13).

In recent years, individuals have become increasingly interested in lycopene due to its potential health benefits (Fig. 2). Specifically, epidemiological studies have reported that the intake and serum levels of lycopene are associated with a reduced risk of certain types of cancer, e.g., breast cancer (14,15). In addition, research has reported the synergistic effect of lycopene and chemotherapy drugs (e.g. docetaxel) or natural compounds (e.g. genistein) (16,17). Furthermore, a novel drug delivery system has previously been employed to improve its bioavailability to further increase its anticancer application (18).

The present review aimed to discuss the current developments that may improve lycopene efficacy in the prevention and treatment of cancer. This includes synergistic effects of lycopene with chemotherapy drugs or nutrients, novel drug delivery systems and relevant epidemiological studies to support the protective role of lycopene in cancer chemoprevention and treatment, and provide important reference value for further development and utilization of lycopene.

Safety is an important issue to be considered for natural compounds. Several studies have evaluated the safety of different doses of lycopene, including acute toxicity studies, sub-chronic and chronic safety studies, reproductive studies and genetic toxicity studies (19,20). A total of ≤3 g/kg/day of different forms of lycopene (namely, lycopene extracted from tomatoes, synthetic lycopene and its crystalline extracts) are generally considered to be safe (21,22) and there has been no report of adverse events associated with the use of lycopene at a normal dose (≤3 g/kg/day) (23). The European Food Safety Authority panel derived an acceptable daily intake of 0.5 mg/kg body weight/day for animals based on a ‘no-observed-adverse-effect level’ for lycopene from all sources (24). Moreover, the US Food and Drug Administration has classed tomatoes and lycopene as ‘Generally Recognized As Safe’ (12,25). However, despite the absence of adverse effects with 150 mg/day intake of dietary or formulated lycopene in healthy individuals (26), it may be controversial to identify the intake as an ‘Observed Safe Level’ due to its short duration of use (one week) (20). Shao and Hathcock (20) proposed a 75 mg/day intake as the upper limit of lycopene for supplements, as no adverse effects were reported from continuous administration of 75 mg/day lycopene in a 4-week clinical study (27,28). Moreover, in several clinical studies, an intake of ≤30 mg/kg lycopene has been employed to generate chemopreventive and therapeutic effects (29–32). However, research has reported that high doses of lycopene supplementation (3.3 mg/kg /day, the equivalent dose to 45 mg/day in humans) and chronic alcohol ingestion can induce the expression of cytochrome CYP2E1 and may promote the harmful effects of excessive alcohol intake (e.g. a higher incidence of hepatic inflammatory foci was found in rats fed both alcohol and high dose lycopene group compared with the other groups) (33). Therefore, further research is warranted with a focus on individuals that consume high amounts of both alcohol and lycopene. Moreover, there have been case reports of lycopenemia which resulted in deep-orange discoloration of the skin due to daily intake of large amounts of tomato juice (180 ml-2 l for >10 years, and restriction of lycopene-containing foods was an effective method of treatment (34,35).

Lycopene is a hydrophobic compound and the presence of water can reduce its solubility and bioavailability (36,37). Moreover, lycopene naturally exists in fruits and vegetables in the form of a trans-isomer, which presents a low absorption rate and bioavailability (11). The bioavailability of lycopene is also influenced by cooking, interactions with other carotenoids and the presence of fat or oil (38). Thermal processing of tomato products can cause changes in the structure of lycopene to shift and yield cis-isomers in the product and this form is more bioavailable (36,39). The presence of fat in food also helps enhance the absorption of lycopene (40) and its absorption is influenced by the amount of ingested fat, and the type and emulsification of dietary fat (41,42). However, it has been recommended to avoid the consumption of lycopene concurrently with high dietary fiber, as several types of dietary fiber (e.g. pectin, guar, alginate, etc.) are associated with lower bioavailability of lycopene (43). In addition, genetic polymorphism also affects the bioavailability of lycopene, wherein a previous study suggested that specific single nucleotide polymorphisms (SNPs) of β-carotene oxygenase 1 (SNP rs6564851 in particular) are associated with greater effective lycopene uptake in humans (44). Currently, novel delivery systems have been developed to improve the bioavailability of lycopene, which are discussed in the present review.

Several studies have reported the anticancer effects of lycopene, which involve the inhibition of proliferation of cancer cells mainly through antioxidant activity, regulation of anti-inflammatory, growth factor signaling and apoptosis induction (4,11,22). By regulating these physiological processes, anticancer effects are exerted by modulating signaling pathways and their crosstalk (Fig. 3). As a natural compound, lycopene has notable advantages such as low toxicity, easy availability and low cost (4,44). In addition to exhibiting antitumor activity when used alone (45), lycopene in combination with other drugs (e.g. docetaxel, enzalutamide, sorafenib) can also enhance anticancer effects or reduce side effects caused by cancer treatment (Table I).

Due to its insolubility in aqueous solvents, lycopene exhibits low bioavailability and stability, which limits its application in cancer treatment (44). To overcome these limitations, researchers have used several delivery systems to load lycopene to improve bioavailability and enhance pharmacokinetic properties (70), and these delivery systems were mainly nanotechnology-based. The use of nanocarriers can promote controlled delivery of drugs to specific target sites without altering their biological activity and pharmacological properties, improving the stability and solubility of lipophilic and hydrophilic bioactive substances in several types of media, which expands the potential of lycopene for drug applications in therapy (71,72). Currently, the use of nanocarriers to encapsulate lycopene mainly involves organic nanosystems based on lipid nanostructures, such as solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and niosomes (NIs).

SLN consist of crystalline lipid matrix that are solid at room temperature and certain tension agents (e.g. poloxamer) enable them to accommodate molecules between the fatty acid chains in the lipid core or surface (73,74). The main advantage of SLN is the use of solid lipids, which reduce the fluidity of drugs in the matrix, prevent particle aggregation, improve stability and enable sustained drug release. Moreover, when administered orally, SLN are absorbed by the reticuloendothelial system and bypass the first-pass metabolism, which thereby increases the bioavailability of drugs (75). Jain et al (76) applied a homogenization-evaporation technique to loaded lycopene with SLN with different ratios of biocompatible viz. compritol ATO 888 and gelucire and evaluated their effect on MCF-7 cells. Compared with free lycopene, a notably higher cellular uptake of lycopene-SLNs was reported in MCF-7 cells and lycopene-SLN markedly decreased the concentration and time dependent cell survival of MCF-7 cells. Moreover, the combination of lycopene-SLNs and methotrexate notably enhanced anticancer activity. NLC is an enhanced carrier of SLN, which replaces certain solid lipids with liquid lipids to form mixed lipids, and maintains them in a solid state at room temperature and body temperature (77,78). Singh et al (79) developed an optimized NLC of lycopene with the encapsulation efficiency and drug loading of 84.5 and 54.0%, respectively, for efficient absorption. Results from ex vivo gastrointestinal tract permeation studies demonstrated lycopene loaded in NLC can enhance the permeation ~4-fold increase in the serosal medium and inhibit P-glycoprotein efflux pump, which aided in the permeation of lycopene through the intestinal milieu for improved absorption (79). Furthermore, lycopene-NLC exhibited strong cytotoxicity against human breast cancer cells (79). As lipid drug carriers, SLN and NLC are widely studied and have the advantage of a relatively simple preparation method and notable encapsulation efficiency and drug loading rate, which should be explored in future research (Table II).

Polymeric nanoparticles (NPs) are composed of encapsulated drugs and polymer excipients, and the surface properties of NPs can be modified by using different polymer end groups or attaching polymers to the surface of NPs (80,81). Targeted ligands, such as antibodies, peptides can also attach to NPs surfaces to allow for specific interactions with tissue components or cell receptors (82,83). Bano et al (84) synthetized thermosensitive polyethylene glycol (PEG)-poly(N-isopropylacrylamide) (PNIPAAM)-PEG-based co-polymeric nanoparticles to encapsule of lycopene and evaluate their in vitro anticancer activity and inhibitory effect on 12-O-tetradecanoylphorbol-13-acetate-promoted skin inflammation and tumorigenesis in Swiss albino mice. Higher doses of PNIPAAM-PEG-lycopene were reported to reduce the percentage of mice bearing tumors to 4.1±0.91 with a 41.4% incidence compared with that of 12.7.4±1.31 with a 97.3% incidence in the model group, which markedly reduced the incidence rate and tumor burden of skin tumors (84). This effect was associated with the inhibition of cyclooxygenase-2, oxidative stress response and the induction of apoptosis. Lycopene loaded with NPs increases aqueous solubility and bioavailability of lycopene, which makes it a promising strategy for the treatment of skin inflammation.

Moreover, whey protein isolate (WPI), a type of amphiphilic material and the semitransparent liquid portion of milk, is obtained by removing the curd after coagulation. WPI is a highly bioavailable protein composed of vitamins and minerals and rich in essential and branched chain amino acids (85,86). WPI can intercept hydrophobic substances superior to commonly used carriers of the same type. Moreover, it is easy to digest and unload its contents under normal gut conditions (87,88). Jain et al (89) developed a novel strategy of formulating lycopene-loaded WPI nanoparticles (lycopene-WPI-NPs) solely using the rational blend of biomacromolecule without the use of equipment-intensive techniques. As lycopene-WPI-NPs can maintain the plasma level of lycopene for a long time, it demonstrated stronger antitumor characteristics against breast cancer compared with free lycopene and in subsequent survival tests, lycopene-WPI-NPs exhibited a superior animal survival rate.

Nanoemulsions are oil-in-water, water-in-oil dispersions stabilized by two immiscible liquids with appropriate surfactants (90,91). Huang et al (92) prepared a lycopene-nanogold nanoemulsion containing Tween 80 as an emulsifier. The nanoemulsion resulted in a 15-fold rise in early apoptotic cells of HT-29 compared with untreated cells, and markedly decreased the expressions of procaspases 8, 3 and 9, as well as poly-ADP ribose polymerase-1 and Bcl-2, whereas an increase in Bax expression was observed. The nanoemulsion was also associated with an upregulation of the epithelial marker, E-cadherin, and downregulated AKT, NF-κB, pro-MMP-2 and active MMP-9 expressions to reverse the invasion-associated markers. Furthermore, the lycopene-nanogold nanoemulsion may hold potential in colorectal cancer (CRC) therapy (92).

Unmodified nanocarriers often fail to achieve specific targeting and efficient antigen presentation (82,83). Therefore, improving their active targeting and stability, and prolonging in vivo circulation time, has become a research hotspot in drug delivery systems. In recent years, the development of several engineered nanocarriers has overcome the aforementioned shortcomings. NI is a new generation of vesicular nanocarriers and provides a multi-lamellar carrier for lipophilic and hydrophilic bioactive substances in the self-assembled vesicle (93). As an alternative to liposomes, NI is considered more chemically and physically stable, especially stable at 25–37°C (94). Kusdemir et al (95) synthesized prostate-specific membrane antigen (PSMA)-targeted NI using a thin-film hydration method followed by bath sonication. Drug-loaded NI [lycopene-indocyanine green (ICG)-NI] were coated with DSPE-PEG-COOH and subsequently anti-PSMA antibodies conjugated to NI (lycopene-ICG-NI-PSMA). The encapsulation efficiency was 45 and 65% upon dual encapsulation of ICG and lycopene, respectively. In in vitro experiments, lycopene-ICG-NI-PSMA selectively increased the anti-proliferative and anti-apoptotic effects on PSMA + LNCaP cells, with a lycopene-ICG-NI uptake rate of 25.67% and a lycopene-ICG-NI-PSMA uptake rate of 41.12% in LNCaP cells, demonstrated the targeted NI displayed improved cellular association and decreased cell viability of prostate cancer cells (95). Evidence showed that the expression of IGF-1R is activated in breast cancer, and its activation through IGF-1 signaling pathway leads to impaired tumor cell proliferation, apoptosis, increased survival rate and resistance to cytotoxic therapeutic drugs (18,96). Thus, Mennati et al (18) loaded lycopene and IGF-1R-small interfering (si)RNA into methoxypoly (ethylene glycol)-poly(caprolactone) hybridized with dimethyldioctadecylammonium bromide cationic lipid nanoparticles to simultaneously deliver lycopene and IGF-1R-siRNA to MCF-7 breast cancer cells. The results demonstrated that the co-delivery of lycopene and IGF-1R-siRNA markedly prevented the growth and proliferation of MCF-7 cells, indicating it may be an effective strategy for the treatment of cancer; however, this study lacked in vivo experiments to confirm this effect.

Moreover, although the development of novel delivery systems provides a potential effective approach for the application of lycopene, several novel formulations (e.g. exosomes) have not been fully utilized to improve the effectiveness of lycopene and certain delivery system studies have only been performed at the in vitro stage, lacking evidence from in vivo studies. The above studies have also only investigated the effectiveness of the novel carriers loaded with lycopene, which lack research on their mechanisms of action. Additionally, although nanomaterials have driven advances in medicine, their toxicity and potential risks are also notable (97). To the best of our knowledge, no nanotechnology delivery systems loaded with lycopene have been approved for marketing to date. Therefore, animal model and epidemiological studies are necessary to provide further evidence for the use of lycopene in the treatment of cancer.

As previously mentioned, SNP variations can affect the bioavailability of lycopene. Therefore, in-depth research on the impact of genetic variations on lycopene plasma/tissue responses may contribute to further understanding of the relationship between natural compounds and health, and guide personalized lycopene therapy. In a meta-analysis of a multiethnic population (African-, Hispanic- and European-American) of postmenopausal women, the scavenger receptor class B, member 1 (SCARB1) gene, which encodes a cholesterol membrane transporter, was markedly associated with serum lycopene level (rs1672879) (120). Furthermore, the slit homolog 3 gene (rs78219687) and the dehydrogenase/reductase member 2 gene (DHRS2; rs74036811) were markedly associated with lycopene concentrations in African-American individuals in the unadjusted model. After adjustment for total cholesterol only, the variants in the DHRS2 region remained notable (120).

Watermelon is a rich source of lycopene and Crowe-White et al (121) performed a randomized controlled crossover study with postmenopausal women which reported that serum lycopene not only exhibited notable therapeutic effect, but also demonstrated marked inter-individual responses, and these were associated with the BCO1 (rs6564851) variant. Moreover, in patients with prostate cancer, different intake levels of tomato-soy juice were reported to affect the BCO1 single nucleotide polymorphism (SNP; rs12934922 and rs6564851) effects in magnitude and direction, but no notable trend of SCARB1 (rs11057841) genotype effect for the prediction of plasma phytofluene level was observed (122). Additionally, in a study with healthy male participants, 28 SNPs in 16 genes were reported to be associated with 72% of the variance in the postprandial plasma chylomicrons lycopene response (123). In addition, the variant of SETD7 (rs7680948) was markedly associated with serum lycopene concentrations in 441 adults. Meanwhile, an association of lycopene levels with a different SNP (rs11057841) in SCARB1 was observed, which provided nominal evidence for previous studies (124). Therefore, the aforementioned results support that genetic variation is an important factor in reflecting differences in lycopene levels between individuals; however, as the studies were performed using single sex populations, sex differences in the association between the genetic variant and serum lycopene concentrations could not be evaluated.

Furthermore, different cancer subtypes defined by certain characteristics (such as menopausal status or expression of genes and proteins status) may have different risk characteristics, which are important factors affecting research results. For example, the ER and PR status is usually used to define the subtype of breast cancer (102). Cui et al (125) studied the association between carotenoids and the risk of hormone receptor-defined invasive types of breast cancer in postmenopausal women. The study reported a lower risk of ER⁺/PR⁺ breast cancer associated with α-carotene, β-carotene and lycopene intakes, when comparing the highest with the lowest quintiles of intake; however, no associations were observed for other breast cancer groups jointly defined by their ER and PR status. Moreover, a meta-analysis demonstrated that lycopene was inversely associated with breast cancer and exhibited stronger associations for ER⁻ compared with that for ER⁺ tumors (126). Stratified analyses by menopausal status and ER/PR status also revealed that serum α-carotene, β-carotene, lycopene and lutein/zeaxanthin were inversely associated with breast cancer risk among Chinese premenopausal women and among all subtypes of ER or PR status (127). An in vitro study has also reported that ER status is an important factor in the response of cancer cells to treatment with carotenoids and retinoids (118).

Therefore, studies that analyze cancer as a single factor may dilute or even mask the effects that may be caused by cancer subtypes. Further research is warranted to explore the relevant genetic variation factors to clarify the exact role of lycopene in cancer. Additionally, the association between the aforementioned genes and lycopene requires large-scale population studies. The ultimate aim of these studies should be to provide an accurate genetic tool to predict individual lycopene bioavailability, obtain the optimal dosage for individuals and regulate disease risk by adjusting the intake of lycopene.

Cancer is a major cause of death worldwide and the development of novel anticancer drugs is an effective means to alleviate this. Lycopene, an easily obtained natural compound abundant in nature, has several health benefits as well as high application prospects and commercial value. Epidemiological data has demonstrated that lycopene is associated with a reduced risk of certain cancer types and with the combination of therapeutic drugs, it may enhance efficacy and antitumor activity. Moreover, novel delivery systems may markedly improve its bioavailability. Lycopene may prove to be an effective strategy for future cancer prevention and treatment; therefore, further study is worthwhile.

Although there is currently a large amount of research evaluating the anticancer effects of lycopene, it is still insufficient to assess its full potential in the field of cancer. Due to instability caused by temperature and other factors, there may be contradictions between in vitro and in vivo research results. In addition, due to differences in dietary patterns and lifestyle habits, further research is necessary to explore effective doses of lycopene and clarify the relationship between beneficial effects and intake. Therefore, translational pharmacology studies are warranted to validate the anticancer activity of lycopene. Furthermore, high-quality clinical trials, such as multi-center, double-blinded, randomized controlled studies are required to assess the effects of lycopene and the synergistic effects with other chemotherapy drugs (e.g. docetaxel, 5-FU, cisplatin). Dietary intake can also affect the bioavailability of lycopene, and the development of novel delivery systems, such as natural carrier of extracellular vesicles, has markedly improved the bioavailability of lycopene. In addition, it is necessary to strengthen the research of lycopene-related SNPs to achieve precision medicine. Perhaps with the precise use of lycopene and with the collaborative application of multiple omics such as genomics, transcriptomics, artificial intelligence and big data, pathway-specific dependencies of lycopene can be elucidated.