The history of grape cultivation is estimated to be 6,000 to 8,000 old, based on archeological and seed findings [1]. The dual utilization of grapes as a delicious fruit and as a source for extensive vine production explains their widespread farming and development. Leaving apart the high commercial value of the grapes in the nutritional and vine industry, grapes consumption is associated with beneficial health virtues. Studies have shown that grapes feeding diminishes the risk of cardiovascular and skin diseases, diabetes, neurodegeneration, Alzheimer disease, obesity, and certain types of cancers [2–4]. These effects result from grapes’ high polyphenol content, of which RSV is the most significant. Plants that produced RSV were significant items in the Asian pharmacopeia, according to Venkat et al. [5].

RSV has demonstrated anti-inflammatory properties by mitigating the harmful effects of reactive oxygen species (ROS), primarily hydrogen peroxide and superoxide radicals [6]. For middle-aged and older people with increased oxidative and anti-inflammatory activity, RSV plays an important role. It was shown that treatment of their peripheral blood mononuclear cells (PBMC) with RSV regulated the production of the pro-inflammatory cytokines IL-6 and TNFα [7]. RSV inhibits the activity of immune recognition receptors (TLR), such as TLR4, which stimulates the inflammatory mediators nuclear factor kappa B (NF-kB) and interferon (IFN) [8]. Given the proven impact of chronic inflammation on the onset and progression of cancer [9,10] and the immune system’s active participation in this process, it is plausible that the immunomodulatory properties of polyphenols play a significant role in cancer prevention. Inflammatory reactions are heightened by malignant processes in general and digestive tract malignancies in particular. This, in turn, activates immune system components such as PBMC, initiating a cross-talk between immune and cancer cells [11].

A comprehensive review of RSV pharmacokinetics has been conducted by Neves et al. [12]. Given orally it is readily absorbed, however, each person’s absorption is different. In the digestive system, it is converted by the intestinal and liver cells into glucuronic acid and sulfate coupled with the phenol clusters and rapidly excreted through the feces and urine suggesting a low bioavailability. To avoid this impediment, efforts have been made to provide its consistent delivery using RSV-loaded nanoparticles which showed encouraging outcomes by inhibition of colon cancer cell migration and triggering apoptosis [13].

RSV may induce cancer cell death through a variety of mechanisms such as apoptosis, pyroptosis, ferroptosis, cuproptosis, necrosis, and more [14]. With an emphasis on digestive tract cancers, the current work aimed to review the immunomodulatory and carcinopreventive effects of RSV in connection to the beneficial effect of polyphenols on the prevention of tumor development.

There is sound evidence that RSV exerts immuno-regulatory functions. RSV reduces the immune cell expression of pro-inflammatory cytokines by inhibiting of toll-like receptor (TLR) [15]. It regulates the immune properties of lymphocyte subtypes having a crucial role in the process of inflammation [16]. RSV induces polarization and immune response of CD8⁺T lymphocytes and the production of cancer preventing IFNγ and TNFα cytokines [17]. Acting on CD8⁺T cells by upregulating the levels of TNFα, IL-2, and IL-12, RSV enhanced their cytotoxic effect, an important step in halting the growth of cancer [17–20]. By upregulating protein kinase B (Akt B) and the mammalian rapamycin target (mTORC2) pathway, RSV enhanced the function of the natural killer (NK) cells that actively participate in the process of carcinoprevention [21].

After being treated with RSV, neutrophils, and macrophages exhibited a concentration-dependent reduction of ROS generation [22]. When unstimulated human PBMC were incubated with RSV, the production of IL-6, IL-1ra, and IL-10 was lowered, while TNFα release was slightly elevated [23]. Conversely, exposing unstimulated RAW-264.7 macrophages to RSV increased IL-10 release and decreased TNFα production [24], indicating that the polyphenol has distinct effects on various macrophage subtypes. When human THP-1 monocytes and macrophages were treated with RSV, a difference in the immune response was seen; although the polyphenol stimulated the pro-inflammatory cascade and inhibited monocyte proliferation by causing cell cycle arrest in the S phase, it also produced an anti-inflammatory burst in THP-1 macrophages [25].

The pro-inflammatory cytokines IL-6 and TNFα were significantly inhibited when lipopolysaccharide (LPS) stimulated macrophages were treated with RSV [26], whereas the generation of the anti-inflammatory cytokines IL-10 and TGF-β was enhanced [27]. Further explanations for the anti-inflammatory activity of RSV treated macrophages include inhibition of NF-kB, Janus kinase, and signal transducers and transcription activators (JAK/STAT), as well as inhibition of IL-6 and TNFα secretion by increased production of cytokine signaling suppressor 1 (SOCS1), being a STAT inhibitor [28,29]. These findings are consistent with the decreased generation of inflammatory mediators achieved with RSV, such as TNFα, IL-8, and monocyte chemoattractant protein-1 (MCP-1) through activation of NF-kB, JAK/STAT, and Janus kinase in LPS stimulated monocytes [30].

Inhibition of vascular endothelial growth factor suppressor (miR-146a), activation of nuclear relation factor 2 (Nrf2), and suppression of hypoxia-inducible factor 1α (HIF-1α) are additional mechanisms to account for the anti-inflammatory activity of LPS stimulated RAW 264.7 macrophages exposed to RSV [31,32]. RSV affects M1/M2 macrophage polarization resulting in the inhibition of pro-inflammatory cytokine production and amplification of the anti-inflammatory ones [17,33,34] in part via adenosine monophosphate-activated protein kinase (AMPK) activation [35]. RSV suppresses the function of the pro-inflammatory M1 macrophages by activation of poly (ADP-ribose) polymerase (PARP), an effect amplified by the addition of nicotinamide [36]. These and other investigations provide strong evidence for RSV’s immunomodulatory function as a carcinopreventer. Fig. 1 illustrates the way RSV induces PBMC to produce anti-inflammatory cytokines that affect cancer cells and the tumor microenvironment.

A considerable number of studies suggest that RSV functions as a suppressor of cancer cell proliferation and has the potential to prevent their spreading to practically all organs [37,38]. Regrettably, while most of the studies have been carried out in vitro or with animal models using various types of cancer cells, clinical research has been conducted mostly on patients with colorectal cancer [39]. In addition to immunomodulatory activity, RSV prevents cancer development by affecting tumor microenvironment and inactivating essential pathways such as NF-kB, the mitogen-activated protein kinase (MAPK), and JAK/STAT that are essential for cancer cells’ development [40–42]. Inhibition of ROS species and pSTAT-3 expression in the gut microbiota by RSV play an important role in carcinoprevention [43].

Cancer development is closely associated with the function of tumor-associated macrophages (TAM). It has been reported that the M2 TAM polarization was affected by RSV due to a significant decrease in STAT3 activity, an effect observed both in lung cancer cells and in a mouse lung cancer model [44]. Promoting M1 to M2 macrophage polarization, lesser production of IL-6, and suppression of STAT3 pathway by RSV was observed in breast cancer cells [45]. Enhanced chemosensitivity, as well as inhibited differentiation, migration, and vascular endothelial growth factor (VEGF) production, were also the result of activated M2 polarization when tumor cells were incubated with RSV, or with the conditioned medium obtained after incubation of M2 macrophages treated with the polyphenol [46]. Additional factors such as angiogenesis, epithelial-mesenchymal transition, and repressing the functions of cancer stem cells targeted by RSV contribute to preventing cancer development and metastasis [47].

Overcoming cancer cells’ radioresistance is another benefit granting RSV the role as an adjuvant to radiotherapy [48]. Moreover, it has been demonstrated that RSV increases the susceptibility of breast cancer cells to talazoparib by simultaneously inhibiting Akt signaling and increasing autophagy [49]. RSV may induce programed cancer cells’ death in 11 different ways [50], the most explored being autophagy, apoptosis, ferroptosis, pyroptosis, cuproptosis, and necroptosis [51] schematically presented in Fig. 2.

Autophagy is a process by which RSV may inhibit cancer cell proliferation and metastasis [52], acting through a number of autophagic signaling pathways [53]. Sirtuin 3 (SIRT3), the protein that maintains mitochondrial homeostasis plays an important role in the regulation of autophagy, a process promoted by RSV in 4T1 breast cancer cells by upregulation of the SIRT3/AMPK autophagy pathway [54]. However, in certain types of cancer, SIRT3 may function as a tumor promoter [55]. Activation of the tumor suppressor nerve growth factor receptor (NGFR-AMPK-mTOR) pathway by RSV promoted both autophagy and apoptosis in A549 non-small lung cancer cells [56]. Restraint of p62 autophagy suppressor and mTOR activation is an additional mechanism by which RSV inhibits cancer progression [57,58]. Autophagy in human leukemia HL-60 cells induced by RSV was found to be dependent on a serine-threonine kinase (LKB1)-AMK and phosphatidylinositol-3-kinase (PI3K)/AKT-regulated mTOR pathways [59].

Apoptosis plays a key role in cancer cells’ death. Depending on the cancer cell type RSV may induce apoptosis triggering a chain reaction by activating AMPK. Consequently, it promotes enhancement of the tumor suppressor TSC2 that inhibits the anti-apoptotic activity of mTOR. Stimulation of apoptotic receptors such as ROS and activation of P53 are additional mechanisms by which RSV sets off the procession of apoptosis [60]. Treating HCT-116WT colorectal cancer cells with RSV at doses >10 µM induced apoptosis by inhibition of the tumor promoter SIRT-1, increasing the expression of P21, P53, and the Bcl-2-associated x protein (Bax-2) [61]. Increased caspase activity and DNA breakdown induced by RSV lead to apoptosis expressed by condensation of nuclear chromatin and nuclear damage [62]. Tumor long non-coding RNAs linked with cell proliferation, spreading, and metastasis are also targeted by RSV [63]. Applied in combination with anti-cancer drugs, RSV increases cancer cells’ chemosensitivity by boosting apoptosis [64].

Ferroptosis, another mode of programmed cell death may be triggered by natural polyphenols including RSV [65]. The primary mechanism leading to ferroptosis is intracellular iron accumulation causing cell damage and death. The main ferroptosis regulators are amino acid transporters that exchange cysteine uptake for glutamate (SLC7A11), glutathione peroxidase 4 (GPX4), p53, NRF2, the heat shock proteins HSPB1, CISD1, the protein-coding FANCD2 and the converter of long-chain fatty acids and coenzyme A into fatty-acid coenzymes (ACSL4) [66,67]. RSV has the potential to cause ferroptosis in colorectal cancer cells through upregulating the formation of glutathione reductase 4 (GPX4), decreasing the expression of the cystine transporter solute carrier family 7 member 11 (SLC7A11), and increasing ROS production and lipid peroxidation [68]. Notably, RSV can enhance ferroptosis by acting as a SIRT inducer [69]. Therefore, activation of ferroptosis by RSV may serve as an additional adjuvant for the therapy of many diseases including cancer prevention.

Pyroptosis is an alternative mechanism of cell death that is seen in various illnesses, including cancer. The role of pyroptosis in cancer cell death initiated extensive research. The process impacts the proliferation, invasion, and metastasis of cancer cells and is triggered by inflammasomes, gasdermin D cleavage, and elevated IL-18 and IL-1β cytokine production [62]. In a recent study, Huang et al. [70] brought attention to the capacity of dietary polyphenols, including RSV, to induce pyroptosis in cancer cells and in those in the tumor microenvironment via different pathways contingent on cancer type. RSV was able to induce pyroptosis by suppressing the activation of the NLRP3 inflammasomes bearing a sensor protein of the NLR family which is one of the key regulators of the inflammatory and innate immune response [71]. Pyroptosis could be enhanced in HT-29 and HCT116 colon cancer cells by certain drugs such as lobaplatin [72].

Cuproptosis is a recently described mechanism that may overcome cancer cells’ drug resistance and leads to cell death by transfer of cupper ionophores into the cells causing cupper accumulation [14] and dysregulation of mitochondrial respiration. Copper overload induces membrane damage, mitochondrial vacuolization, chromatin condensation, and finally cell death [73]. The effect of cuproptosis is closely associated with the activity of the ferrodoxin 1 (FDX1) gene which is downregulated in several types of cancers. Low FDX1 expression correlates with poor prognosis [74]. Copper ions activate the PI3K pathway which in turn suppresses Akt activation [75]. According to Wang et al. [76], cuproptosis dependent on a number of copper-related genes is one of the causes of lung carcinoma cell viability, their detection being of prognostic value. Interestingly, copper-induced cell death caused by curcumin has been reported in HCC cells [77], but elucidating the effect of RSV and other polyphenols on cuproptosis in cancer cells, in general, presents a challenge.

Necroptosis. Galluzi et al. [78] defined necroptosis as a type of programmed cell death dependent on serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL). The authors highlighted the molecular mechanisms governing the process in a variety of diseases including malignancies. Because research suggests that necroptosis can function as both a tumor promoter and an inhibitor, its exact role in tumorigenesis is not fully clarified [79]. According to Lee et al. [80] RSV reduced the viability of LNCap prostatic cancer cells by activation of both necroptosis and apoptosis by raising the receptor interacting protein 3 (RIPK3) and mixed-lineage kinase domain like (p-MLKL) levels. This effect was more pronounced when the cells were treated with both RSV and docetaxel.

Future studies must clarify the mechanisms by which RSV causes cancer cell death and the dosage required to accomplish this objective in humans.

Inhibition of cancer cells’ proliferation and migration and achieving their death should be essential goals in cancer treatment strategy. Unfortunately, cancer remains a challenging disease to treat even with major advancements in immune- and chemotherapy. The review presented herein provides significant insights into the mechanisms by which RSV demonstrates its anti-tumor properties. Notably, elucidating certain constraints of RSV as an anticancer agent, like inadequate pharmacokinetics, and lack of appropriate dose in humans, ought to showcase upcoming viewpoints [122]. Clarifying RSV’s benefits for cancer treatment will require addressing the low bioavailability issue and finding new methods to deliver RSV to the cells. A combination of anticancer drugs with plant polyphenols such as RSV, expressing both immune and anti-proliferative activities could be a feasible adjuvant in the anti-cancer pharmacopeia. It is necessary to move from in vitro experiments to further animal and clinical studies to achieve this goal.