Anticancer peptides can be generated by rice and soy protein hydrolysis, specifically through the process of alcalase digestion of rice bran proteins. This discovery established a fundamental basis for the potential utilization of these protein hydrolysates in cancer prevention strategies (36). A study has reported the identification of five peptides (GLTSK, LSGNK, GEGSGA, MPACGSS and MTEEY) obtained from a common bean that exhibited antiproliferative properties on human colon cancer cell lines (HCT-116, RKO, and KM12L4). The peptides were found to affect the activity of enzymes regulating cell proliferation, consequently inducing cell cycle arrest and further apoptosis (21). An ACP with a molecular weight of 1.155 kD, derived from chickpeas, hydrolysis by Flavorzyme has been demonstrated to possess anti-proliferative properties in breast cancer cell lines, specifically MDA-MB231 and MCF-7. This effect is achieved by upregulating the expression of the P53 protein (37), usually activated by different cellular stresses (i.e., DNA damage), and regulating cell cycle progression and death pathways. The peptide sequences SSDEEVREEKELDLSSNE and KELPPSDADW, which were investigated in a study conducted by Karami et al. and obtained from wheat germ protein, had cytotoxic effects on A549 lung cancer cells. The IC50 values for these peptides were measured to be 2.34 μM and 7.25 μM, respectively (38). M. Li et al., reported the dose- and time-dependent cytotoxic activity of papain-hydrolyzed mung bean protein against hepatocellular carcinoma (HepG2) cells with an IC value of 2.99 mg/mL. The authors confirmed that peptides isolated from mung bean protein (Val-Glu-Gly, Pro-Gln-Gly, Leu-Ala-Phe, and Glu-Gly-Ala) could induce apoptosis in hepatocellular carcinoma (HepG2) cells. While high doses may stop cell cycle at the G0/G1 phase and inhibit its progress to the S phase, low concentrations suppress the cell growth during S phase (39). Similarly, glutamic acid from pepsin/trypsin-digested germinated soybeans also showed dose-dependent in vitro antiproliferative effects on Caco-2, HT-29, and HCT 116 human cancer cells (40). Peptides extracted from black soybean, mung bean, and adzuki bean have demonstrated the ability to inhibit cancer cells within a concentration range of 200-600 µg/ml (41). Zheng et al. in their study documented the utilization of alcalase and trypsin for the enzymatic hydrolysis of D. catenatum to extract nine distinct peptide fractions. Among these fractions, it was noted that fraction A3 exhibited the highest level of antiproliferative activity against liver (HepG-2), gastric (SGC-7901), and breast (MCF-7) cancer cell lines and the development inhibition rate of cytotoxicity reached a peak of 70%. Notably, the A3 fraction contained three peptides that were abundant: RHPFDGPLLPPGD (1.416 kDa), RCGVNAFLPKSYLVHFGWKLLFHFD (2.994 kDa), and KPEEVGGAGDRWTC (1.504 kDa), and displayed significant pro-apoptotic effects (42). Bioactive peptides derived from Phaseolus vulgaris, soybean meal, amaranth, and seaweed have demonstrated anti-cancer, antioxidant, and cytotoxic properties (22, 24–27, 29), showing potential for complementary utilization in conjunction with conventional cancer therapies. Lunasin is a bioactive peptide derived from soybean or wheat, has been the focus of extensive studies exploring its potential anti-cancer properties (30). Other soy protein peptides exhibit anticancer properties, although their potency is comparatively lower than that of Lunasin (43). The anticancer properties of Lunasin are contingent upon its unique amino acid sequence, which encompasses Arg-Gly-Asp for cellular adhesion and the bending of the polyaspartate acid chain consisting of nine aspartic acid residues. Research findings indicate that Lunasin exhibits promising potential as an adjuvant therapy for cancer and may serve as an effective agent against inflammation, tumor growth, and metastasis in various cancer types (44, 45). Lunasin may potentially serve as a chemo preventive agent in mitigating the incidence of colorectal cancer, breast cancer, and other related malignancies. This function can be executed via various modes and has the capability to impede the interaction between adipocytes and neoplastic cells. Adipocytes, or fat cells, are essential for energy storage, hormone regulation, and overall metabolic health. They play a role in obesity-related health issues and are central to understanding conditions like diabetes and cardiovascular disease. Neoplastic cells, on the other hand, are cancer cells and are crucial in cancer research and treatment. Studying neoplastic cells informs early detection methods, advances in personalized cancer therapies, and strategies for cancer prevention. Both adipocytes and neoplastic cells have far-reaching implications for public health and medical progress, with adipocytes impacting metabolic health, and neoplastic cells being pivotal in the fight against cancer (46, 47). The incorporation of Lunasin into the rice genome yields Lunasin-rich rice, which is anticipated to serve as a functional food for cancer patients (48). The potential integration of Lunasin into the rice genome has been acknowledged as a promising strategy for developing useful food options targeted at individuals affected by cancer.

In a recent study, two short peptides Trp-pro-pro and Gln-Pro have been isolated from the protein hydrolysate of blood clam (Tegillarca granosa) muscle through a combination of ultrafiltration and successive chromatographic techniques. The authors demonstrate that Trp-Pro-Pro might be employed to counteract the surplus generation of reactive oxygen species (ROS) during oxidative stress situations and mitigate the risk of cancers resulting from the accumulation of excessive free radicals within cells. The peptides demonstrated noteworthy cytotoxic properties against diverse cancer cell lines, namely PC-3 (human prostate), DU-145 (human prostate), H-1299 (lung), and HeLa (cervical), in a dose-dependent fashion. Additionally, the treatment with the peptides resulted in notable morphological changes in PC-3 cells (32). Theansungnoen et al. conducted an experiment on cervix cancer cell lines, specifically HeLa and CaSki. They examined the effectiveness of two peptides KT2 (NGVQPKYKWWKW) and RT2 (NGVQPKYRWWRWWR RWW), obtained from freshwater crocodile, and found that they can cause the death of HeLa cells (28). Su et al. in their research involving the utilization of 8 kDa anticancer peptides derived from goat spleen, have shown a notable suppression in the proliferation of HCT116 cells (a type of human colon cancer cells) following a treatment duration of 4-6 days. Furthermore, it was observed that these particular anticancer peptides increased cancer cell apoptosis after a 6–12-hour treatment. This apoptosis induction happened by upregulating the expression of poly (ADP-ribose) polymerase (PARP) and p53 and downregulating the expression of Mcl-1 (31). Chalamaiah et al. discovered that protein hydrolysates (PH) derived from rohu eggs had antiproliferative properties. The study conducted hydrolysis using pepsin on a colon cancer cell line called Caco-2. The findings indicated that the pH had an inhibitory effect on Caco-2 cells, with the strength of the effect increasing with the dosage (23). Chi et al. extracted two peptides from the muscle of the blood clam. One of the peptides was identified and its sequence was determined. WPP (398.44 Da) exhibited potent cytotoxic effects on PC-3 (human prostate), DU-145 (human prostate), H-1299 (lung), and HeLa (cervical) cancer cell lines in a dose-dependent manner. Furthermore, WPP induced significant morphological changes in PC-3 cells also WPP demonstrated the ability to eliminate excessive reactive oxygen species (ROS), thereby preventing the formation of cancers caused by an abundance of free radicals (32). Milk proteins have also been documented as exceptional reservoirs of anticancer peptides. An analysis of Himalayan cheese fermented with probiotic strains of Lactobacillus plantarum NCDC 012, Lactobacillus casei NCDC 297, and Lactobacillus brevis NCDC021 has revealed significant in-vitro anticancer activity on various cancer cell lines, including human breast cancer (MCF-7), colon cancer cells (HCT-116), transformed human embryonic kidney cells (HEK-T), and neuroblastoma (IMR-32). This activity is primarily attributed to the production of bioactive peptides during fermentation with the added probiotics (49). Ayyash et al. (2018) examined the anti-proliferative effects of camel and bovine milk that had been fermented by probiotic strains of L. acidophilus DSM9126 and Lactococcus Lactis KX881782. The research group discovered that camel milk, when fermented with Lc. Lactis KX881782, had stronger anti-proliferative effects against cervical cells (HeLa), colon cancer cells (Caco-2), and MCF-7 cancer cells compared to bovine milk. The reduction of proliferation exhibited a robust positive association with the proteolytic activity and DPPH scavenging ability of camel milk that was fermented with L. acidophilus, which is accountable for its anti-cancer properties (50). In a study conducted by Yang et al. researchers found that when roe protein from Epinephelus lanceolatus was broken down using protease N, the resulting hydrolysates showed antiproliferative effects on two human oral cancer cell lines (Ca9-22 and CAL 27). These effects were achieved by inducing apoptosis and halting cell cycle progression at the sub-G1 phase (51). Dolastatin 10 is a short peptide comprising five residues that incorporate non proteogenic amino acids (52). This peptide derived from a marine mollusk demonstrated antimitotic characteristics by inhibiting the polymerization of tubulin, suggesting its potential as an agent for anticancer treatment. Dolastatin 10 is classified among a diverse array of marine-derived bioactive compounds that exhibit antineoplastic properties through the inhibition of microtubule growth (53–55). Much like Hemiasterlins, a class of linear peptide derivatives obtained from a marine sponge, Dolastatin 10 also exhibits these characteristics. Research suggests that Dolastatin 10 and Hemiasterlins share similar functions and display encouraging attributes. Su’s team identified an anticancer bioactive peptide-3 (ACPB-3) (56, 57) derived from the spleens or livers of goats. It demonstrates anti-cancer properties against human gastric cancer cell lines (BGC-823) and gastric cancer stem cells (GCSCs), both in laboratory settings and in living organisms. This includes the ability to limit the proliferation of BGC-823 cells and CD44⁺ cells in a manner that is dose dependent, as well as boosting the tolerance to chemotherapy in mice. ACBP-3 also inhibits tumor growth in living organisms (57, 58). Guha and his colleagues discovered TFD-100, a 100 KDa Thomsen-Friedenreich (TF) glycopeptide containing a TF disaccharide (TFD) which can bind to galactin-3, a lectin that specifically binds to β-galactosides. Furthermore, TFD-100 has been shown to prevent the adhesion of androgen-independent prostate cancer cells (PC3), as well as angiogenesis and galactin-3-induced T-cell death (59). Bioactive peptides obtained from diverse origins possess promising potential as agents for combating cancer. However, additional investigation is necessary to comprehensively elucidate their underlying mechanisms of action and ascertain their prospective clinical utility.

Venoms are enriched reservoirs of bioactive peptides that can be utilized for the creation of novel pharmaceutical compounds. However, due to their toxicity, many venoms necessitate chemical alterations before they can be safely employed, and the intricate procedure requires substantial cost and time. Peptides found in venom can interact with certain biological components. This offers potential for the development of new medications that can target prevalent diseases like cancer and neurological disorders (60). The intricated and expensive endeavor of manufacturing novel medications from toxins necessitates substantial financial commitment, especially throughout the clinical stages of II and III, with no assurance of success (60).

Several biologically active peptides found in scorpion venoms exhibit potential anti-cancer properties both in in vitro and in vivo. One of these peptides has successfully completed phase I and phase II clinical trials (61, 62). The venoms of snakes, scorpions, spiders, honeybees, and cone snails contain bioactive peptides that show potential as abundant reservoirs of chemotherapeutic agents for various human diseases, including chronic inflammation, autoimmune disorders, and cancer (63–66).

Peptides and proteins are crucial macronutrients that provide the necessary building blocks for protein synthesis and are recognized as a significant energy source (108). Moreover, proteins and peptides present in food can exhibit diverse biological functionalities. Bioactive peptides are obtained from animal and plant proteins through diverse techniques such as proteolysis within the intestinal tract, enzymatic or chemical hydrolysis, or microbial fermentation (19, 109). Immunomodulatory peptides are a type of bioactive peptides that encompass constituents responsible for the regulation of immune cell activity, cytokine generation, and antibody production (110). The immunomodulatory and anticancer properties of these substances are contingent upon their amino acid composition, sequence, and length, as stated in reference (19). These peptides exhibit varying effects on the cell proliferation, inflammation, and cellular protection or destruction, depending on the specific level of action (111–113). Therefore, due to their unpredictable effects on both innate and adaptive immune cells, immunomodulatory peptides are currently a topic of investigation. Depending on whether they stimulate or repress immunological responses, they can operate as either immunostimulants or immunosuppressants. As a result, they hold potential for therapeutic applications in disease treatment (15, 114). The determination of the mechanisms of immunomodulatory peptides functions supplies new opportunities for cancer treatment through improving the immune system. So, this part provides a brief overview of several bioactive peptides from plant and animal sources have been used to modify the immune responses.

Plants are an excellent source of valuable bioactive peptides with various functions. Previous researchers have investigated the immunomodulatory effects of some peptides from plants that are widely used in the human diet like rice, wheat, and legume. Table 2 indicates several of these bioactive peptides. Macrophages, as innate immune cells, can phagocyte cancer cells and pathogens. In addition, they can interact with other constituents of the innate and adaptive immune system to augment their activities, like secretion of cytokines and cytotoxicity (128). Therefore, regulation of macrophage’s function by immunomodulators would ameliorate the ability of host immune response against cancer. Wu et al. conducted an evaluation of the immunomodulatory effects of the peptide [Glu-Cys-Phe-Ser-Thr-Ala (ECFSTA)] derived from wheat germ globulin on macrophage RAW 264.7 cells (129). The findings of this study indicated that the peptide ECFSTA could enhance cell phagocytosis function and the secretion of nitric oxide (NO), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), IL-1β, and reactive oxygen species (ROS) generation by RAW 264.7 cells through activation of toll-like receptor 4 (TLR4) and TLR2 (115). In another investigation, Defatted Wheat Germ Globulin was hydrolyzed with different enzymes, including Alcalase, Neutrase, Papain, Pepsin, and Trypsin. Alcalase-prepared peptides were found to exhibit the greatest immunomodulatory activity in relation to lymphocyte proliferation, phagocytosis, and pro-inflammatory cytokine production in RAW 264.7 cells, as mentioned in a previous study (116). In addition to macrophages, it was reported that wheat peptide can modify NK cells and T cells activities. For example, N. Horiguchi et al. demonstrated an augmentation in NK cell function after further administration of one gram of wheat gluten hydrolysate after each meal for six days in healthy people (117). NK cells play important roles in elimination or control of viral infections and cancer cells. NK cells act against tumor cells with cytotoxic role and also secretion of cytokines, mainly interferon-γ (IFN-γ), to regulate adaptive immune responses (130). Treatment of cell culture supernatants from PHA-stimulated human PBMCs with Alcalase wheat gluten protein hydrolysates (WGPHs) resulted in reduction of Th1 and Th17 cytokines secretion (IFN-γ and IL-17, respectively). Although IL-4 levels were not changed but the ratios of IL-4/IFN-γ, IL-4/IL-17 and IL-10/IFN-γ were significantly increased (118). It was shown that rice protein hydrolysates (RPHs) through trypsin digestion may potentially serve as a source of immunostimulatory peptides on RAW 264.7 cells. The study conducted by Xu Z et al. revealed that the YGIYPR peptide derived from rice protein hydrolysates which stands for Tyr-Gly-Ile-Tyr-Pro-Arg has the potential to enhance the proliferation of RAW 264.7 cells (119). While another study investigated anti-inflammatory effect of rice peptides on RAW264.7 cells. They employed both immuno-prediction and in silico simulation techniques to scrutinize rice peptides with potential immunomodulatory properties. Out of 3630 sequences, it was observed that the amino acid sequences GBP1 (NSVFRALPVDVVANAYR), PEP1 (GIAASPFLQSAAFQLR), LR13 (LLPPFHQASSLLR), and TK17 (TPMGGFLGALSSLSATK) exhibited the greatest affinity towards MHC-II. The immunomodulatory properties of four peptides were verified in LPS-induced RAW264.7 cells and they were found to decrease the secretion NO, IL-6, TNF-α, and IL-1β (120, 131). Various legume proteins contain valuable bioactive peptides (132, 133). Several biological effects of them have been reported, including antihypertensive, antimicrobial, antioxidant, anti-inflammatory, and anticancer properties (134–136). Mung bean and soybean are widely utilized legumes that are rich in polyphenols and antioxidants. The study conducted by Ali, NM et al. aimed to evaluate the immunomodulatory, cytotoxic, and antioxidant properties of both fermented and non-fermented mung bean and soybean. The findings of the study indicated that both fermented soybean and mung bean have the ability to induce splenocyte proliferation and promote the release of serum IL-2 and IFN-γ (121). IL-2 is a pro-inflammatory cytokine that plays a crucial role in enhancing T cell proliferation and promoting the release of interferon-gamma (IFN-γ). IFN-γ is primarily produced by Th1 cells, CD8+ T cells, and NK cells, playing a significant role in stimulating cellular immunity. Consequently, it contributes to the elimination of tumor cells (137). According to Kong et al. hydrolyzed soy protein with different proteases generate peptides with various molecular weight and charge. It was found that alcalase soy protein peptides possess higher positive charge and lower molecular weight. These peptides have the most immune-stimulating property by boosting the phagocytic function of macrophages and manipulation of murine spleen lymphocytes (138). In another study, peptide derived from soybean fraction that underwent peptidase R hydrolysis exhibited mitogenic activity and demonstrated a noteworthy increase in the number of IL-12+ CD11b+, IFN-γ + CD49b+ (NK cell), and IFN-γ + CD4+ (Th1) cells in mouse spleens, as well as the activation of cytotoxic activity in spleen cells against the human erythroleukemia cell line (K562). Furthermore, the analysis of DNA microarray revealed the upregulation of genes associated with innate immune response in Peyer’s patch cells of mice administered with peptides (123). Lunasin is a 43 amino acids peptide derived from soy, which possesses anti-cancer and hypocholesterolemic properties (29). In context of immunomodulation displayed that Lunasin-enriched soybean extract (LES) has the intriguing capability to induce both pro-inflammatory and anti-inflammatory activities within the immune system. This observation comes from a study conducted by Paterson and colleagues. Specifically, when macrophages were exposed to LES, they exhibited increased phagocytic activity and elevated production of NO, IL-6, IL-1β, and IL-10. Furthermore, the study found that Lunasin and LES peptides also stimulated EL4 lymphocytes and prompted the secretion of IL-4, IL-5, and IL-10 cytokines. This suggests that soybean peptides, such as Lunasin and LES, have the remarkable ability to modulate or regulate both the innate and adaptive arms of the immune system. In essence, they possess the potential to modulate immune responses in different conditions (122).

There are some reports from peptide of other less common plants. For example, the utilization of proteins extracted from Pseudostellaria heterophylla can serve as a dietary supplement for enhancing immune system function. The digestion of P. heterophylla protein has yielded a novel peptide induced the TLR2/NF-κB pathway. This peptide has been observed to induce a significant increase in TNF-α production, pinocytosis, and TLR2 expression in macrophages (124). The peptides derived from enzymatic hydrolysate of Coix glutelin, exhibit immunomodulatory properties by inducing proliferation of splenocytes in mice and stimulating the production of NO from Raw264.7 cells in a dose-dependent manner as demonstrated by Ling-Ling. Additionally, it has the potential to inhibit excessive activation of cells triggered by LPS (139). According to a study conducted by Velliquette et al., the anti-inflammatory and immune-modulating properties of peptides derived from sunflower protein with Flavourzyme enzyme has been revealed. These peptides attenuate the activation of NF-κB while enhance the expression of surface markers like CD14 and CD86, which are linked to a dendritic cell (DC) phenotype (127). The activation of monocyte and macrophage, humoral and cell-mediated immune responses, as well as hemopoietin, were observed to be stimulated by peptides derived from Chlorella vulgarian 87/1 (125). In addition, Chan-Zapata et al. have extracted bioactive peptides from the seeds of Salvia hispanica L. that exhibit anti-inflammatory properties. These peptides have been found to significantly reduce the levels of NO, TNF-α, IL-1β, and IL-6, while do not affect the viability of BALB/c peritoneal macrophages (126). Overall bioactive peptides derived from plants can influence immune responses to a variety of situations, potentially promoting both inflammatory and anti-inflammatory actions in diverse contexts as needed. Further research may provide the potential applications of plants bioactive peptides in modulating of immune function in cancer, alleviating autoimmune diseases, and mitigating tissue damage in inflammatory conditions.

Previous in vivo and in vitro studies have reported that bioactive peptides derived from animal sources have the ability of regulating the immune responses, as evidenced in Table 3 . Among dietary proteins, fish, milk, egg, and chicken proteins are likely valuable source of bioactive peptides in nutritional perspective. The immunomodulatory activity of peptides found in certain fish families has been observed to potentially result in heightened lymphocyte proliferation and macrophage activity, as well as improved natural killer (NK) cell function and cytokine production (140, 155). The lymphocyte proliferation, NK cell activity, CD4⁺ T helper cell count in the spleen, and the production of Th1 (IL-2, IFN-γ) and Th2 (IL-5, IL-6) cytokines in mice were enhanced by marine oligopeptides (MOP), which are low-molecular-weight peptide compounds derived from Chum Salmon (140). These findings suggest that MOP may help the inhibition of tumor growth or metastasis through the activation T cells and NK cells as main mediators against cancer cells. Wang YK and colleagues showed that oyster hydrolysates effectively inhibited the growth of transplantable sarcoma-S180 in BALB/c mice. Additionally, these hydrolysates were observed to enhance the proliferation of lymphocytes in the spleen, as well as the activity of NK cells and the phagocytic activity of macrophages in mice. Thus, it is possible to utilize oyster hydrolysates as a nutritional supplement for the purpose of tumor therapy, as suggested by previous research (141). In addition, the immunomodulatory activities of peptides derived from Labeo rohita egg - were assessed on both innate and adaptive responses in BALB/c mice by Chalamaiah et al. Trypsin hydrolysates peptides have been found to have a significant impact on splenic CD4⁺and CD8⁺ T cells while pepsin hydrolysate enhanced the production of mucosal IgA, macrophage phagocytose capacity as well as NK cell cytotoxicity. As a result, divers rohu egg protein hydrolysates have the potential to stimulate different immune cells (143). Milk proteins, comprising of approximately 80% casein and 20% whey proteins such as α-lactalbumin, β-lactoglobulin, are considered a significant source of bioactive peptides that possess various health-promoting properties such as anti-microbial, anti-hypertensive, anti-oxidative, and anti-diabetic activities (44, 156). The presence of multiple immunomodulatory peptides that can either suppress or stimulate an immune response has been demonstrated (157, 158). According to Chen et al. the administration of milk-derived peptides at a dose of 200 mg kg⁻¹ in mice resulted in the most effective regulation of LPS-induced inflammation. This was achieved through the enhancement of immune activity in the spleen and the regulation of immunoglobulin and cytokine secretion (149). The peptide LFP-20, which consists of 20 amino acids and is derived from porcine lactoferrin, can balance Th1 and Th2 response by regulating the expression of Th1 cytokines (IL-12p70, IFN-γ, TNF-α) and Th2 cytokines (IL-4, IL-5, and IL-6), as well as CD3⁺CD8⁺ T cells and B cells, in cases of immune disorder induced by LPS. Although LPS induced remarkable enhancement in production of TNF-α, IL-6, IFN-γ, IL-12p70, IL-4 and IL-5, treatment with LFP-20 declined LPS-induced cytokine secretion (147). Moreover, research has represented that peptides derived from whey and casein proteins play a significant role in regulating the immune system (159). For example, in a study conducted by Rodrıguez-Carrio et al., it was observed that whey β-lactoglobulin fractions, comprising of short peptides, induced the secretion of TNF-α by monocytes. On the other hand, fractions containing large peptides were found to enhance the Th1 cytokine IFN-γ (144). Certain peptide derived from casein generated by strains of Lactic acid bacteria during the process of fermentation have demonstrated the ability to modulate the immune system. The findings of the study revealed that specific peptide fractions derived from fermented milk were capable of inducing the secretion of the anti-inflammatory cytokine IL-10 in human THP-1 monocytes (146). Another peptide from bovine αS1-casein (residues 142-149) significantly increased IFN-γ secretion from CD8+ T cells (160). Therefore, milk peptides may be beneficial in cancer treatment by modifying host immune responses. The egg white has been shown to contain bioactive peptides that play a crucial role in maintaining the viability of the yolk’s embryo (161). The immunoregulatory impact of egg white peptides (EWP) on RAW264.7 macrophage cells and an immunosuppressive BALB/c mice model was evaluated by Zhang, F. et al. The findings obtained from the in vitro experiments indicated that the administration of 100 μg/mL EWP resulted in a significant increase in macrophage activation and the secretion of NO, IL-6, IL-10, and TNF-α in RAW264.7 cells. Additionally, an increase in the production of cytokines such as IL-2, IL-6, IL-10, and TNF-α by splenocytes and peripheral blood leukocytes was observed in mice administered with a dose of 150 mg/kg/day of EWP (148). Another study was conducted to investigate the immunomodulatory impact of peptides derived from Selenium-enriched EWP (Se-EWP) on mice that had been immunosuppressed due to cyclophosphamide administration. The group of mice that received the Se-EWP exhibited elevated levels of white blood cells and serum concentrations of IL-6, IL-2, and TNF-α when compared to the EWP groups like pervious research (162). Hence, it is plausible that EWP could potentially serve as a significant factor in mitigating immune-mediated damages and ameliorating the effects of an immunocompromised condition. The hydrolysates of ovalbumin, lysozyme, and whole egg were found to have an inhibitory effect on lymphocyte proliferation and the generation of IL-10 and IL-13. Additionally, these hydrolysates were observed to reduce the TNF-α production from Th1 cells. Furthermore, they were found to inhibit IgG1-class switching induced by LPS and neutralize the release of ROS (150). Thus, the substance in question possesses the ability to serve various functions, including but not limited to acting as an immunostimulant or immunosuppressant and as a mediator for shifting between Th1 and Th2 responses. Chicken is another common nutrient with bioactive peptides. The immunomodulatory function of chicken collagen peptides is attributed to their ability to regulate the secretion of cytokines that promote inflammation. Zhang et al. reported a decrease in the secretion of IL-6, TNF-α, and soluble intercellular adhesion molecule-1 in mice that had received chicken collagen hydrolysate (151). The pathogenesis of osteoarthritis involves the activation of the inflammatory cascade through the stimulation of various cytokines such as TNF-α, IL-10, IL-8, and IL-1β. The study found that the hydrolysis of trypsin in chicken cartilage resulted in a reduction of these cytokine in papain-induced model rats, leading to an alleviation of osteoarthritis symptoms (152). The silkworm pupa (Bombyx mori) protein is rich in valuable peptides. It has been used as food and medicine in East Asian Countries (163). Enzymatic hydrolysates of silkworm have demonstrated antioxidant, antitumor and anti-bacterial effects (164, 165). Assessment of immunomodulatory peptides derived from silkworm pupa indicated the administration of 100 μg/ml of identified hexapeptide (PNPNTN) obtained from the alcalase hydrolysate resulted in a significant improvement of Con A- or LPS-induced splenocyte proliferation. The physicochemical properties of this hexapeptide like length, positive charge and hydrophobicity affect its proliferative role. Therefore, novel immunomodulatory peptides are potential therapeutic agent for enhancing immune cell function in the context of food ingredients (153).

The venoms of spiders represent a valuable source of bioactive peptides. Munhoz J et al. conducted an analysis on the effectiveness of SNX-482, a peptide obtained from the venom of African tarantula Hysterocrates gigas, on bone marrow macrophages. The administration of SNX-482 resulted in the activation of M0-macrophages, leading to an increase in the expression of costimulatory molecules such as CD40, CD68, CD80, CD83, and CD86. Additionally, the expression of checkpoint molecules including PD-L1, CTLA-4, and FAS-L was also upregulated, regardless of the administered dosage. Furthermore, it was observed that there was an augmentation in the anticancer response as a result of the upregulation of CCR4, IFN-γ, GZMB, and PDCD1 genes, as well as the secretion of IL-23 (154). So, peptides extracted from venom are likely to be used as adjuvants for improving immunotherapies of cancers. Finally, since previous studies highlight the immunomodulatory applications of different bioactive peptides from animals, they have the potential to serve as immunostimulatory or immunosuppressive agents for the treatment of various diseases like cancers, either independently or in conjunction with other therapies.

These peptides have been derived from various sources, including elastin-derived peptides (EDPs), venoms, and neuropeptide Y (NPY). EDPs released in the extracellular microenvironment during tumoral remodeling of the stroma stimulate cancer cell migration by interacting with their membrane receptor, ribosomal protein SA (RPSA) (167). In pancreatic ductal adenocarcinoma (PDAC), EDPs have been shown to promote cell migration by stimulating the transient receptor potential melastatin-related 7 (TRPM7) channel in human pancreatic cancer cells (167). Bioactive peptides from animal venoms have also been found to affect cancer cell features such as cell proliferation, invasion, migration, and immune response modulation. These peptides selectively target cancer cells without harming normal cells and have been proposed as potential therapeutics for aggressive and deadly brain tumors like glioblastoma (GB) (168). However, these peptides, sometimes, have negative effects and support tumor progression. For example, Bombesin is a bioactive peptide, originally isolated from the skin of the European fire-bellied toad (Bombina bombina) (169) that plays a role in modulating cell migration, particularly in the context of cancer progression. It is a neuropeptide that is highly expressed and secreted by neuroendocrine cells in prostate carcinoma tissues and is believed to be related to the progression of this neoplastic disease (170). In a study on 3T3 and lung fibroblasts, bombesin was found to stimulate cell migration in a time and concentration-dependent manner (171). These results indicate that bombesin may play a role in the cellular processes that are crucial for the advancement of cancer, specifically spread and migration. Overall, bioactive peptides from animal sources may have undesired effects on cancer cell migration and other cancer-related processes.

A study showed that hemp peptides, generated by controlled hydrolysis of hemp proteins, exhibited anticancer properties in Hep3B human liver cancer cells. The treatment with hemp peptides increased apoptosis, reduced cell viability, and reduced cell migration in Hep3B cells without affecting normal liver cells. Increased cellular ROS levels, overexpression of cleaved caspase 3 and Bad, and downregulation of antiapoptotic Bcl-2 were all linked to the anticancer effects of hemp peptides. The study also suggested that the Akt/GSK-3β/β-catenin signaling pathway played a critical role in the anticancer properties of hemp peptides (172). Cyclotides are a family of plant-derived cyclic peptides that exhibit a diverse range of bioactivities, such as antimicrobial, anticancer, and anti-HIV properties. They are known for their unique structure and stability, and there exists a considerable potential for the utilization of this substance in the field of pharmaceuticals. Cyclotides have been shown to target cell membranes, which play a crucial role in their mechanism of action (173). In the context of cancer, cyclotides have demonstrated cytotoxicity against various cancer cell lines. Their high stability, small size, oral bioavailability, and tolerance to amino acid substitution make them an ideal platform for designing peptide-based drugs for cancer treatment (17). Some cyclotides are toxic to cancer cells whereas others can be designed to bind and inhibit particular cancer targets. The toxicity of cyclotides is associated with their ability to target and disrupt lipid bilayers containing phosphatidylethanolamine phospholipids (174).

Further research is needed to better understand the specific mechanisms by which cyclotides modulate cell migration and their potential applications in cancer therapy. However, their unique properties and ability to target cell membranes make them promising candidates for the development of peptide-based drugs for cancer treatment.

Flavokawain is a bioactive compound found in the kava-kava plant (Piper methysticum) and has been shown to possess anti-cancer properties (175). Although there is limited information on the direct role of Flavokawain as a bioactive peptide in the modulation of cell migration, some studies have demonstrated its potential in affecting cell migration and invasion in cancer cells. For instance, Flavokawain A (FKA) has been shown to induce apoptosis in breast cancer cell lines MCF-7 and MDA-MB231 and inhibit the metastatic process in vitro. FKA selectively promotes cell cycle arrest in these cell lines and induces apoptosis in a dose-responsive way through the internal mitochondrial route, indicating that FKA’s anti-cancer effect is reliant on the presence of p53 (175). Another study looked at FKA’s ability to protect endothelial cells from the oxidative stress that ochratoxin A (OTA) causes in in vitro models. FKA was found to reduce inflammation via NFκB inhibition and enhance the phosphorylation of PI3K and AKT, which could stimulate antioxidant activity and antiapoptotic signaling. in human umbilical vein endothelial cells (HUVECs). Depending on the dose under the oxidative stress induced by OTA, FKA also increased the phosphorylation of Nrf2 and the expression of antioxidant genes, such as HO-1, NQO-1, and GCLC (176). Further research is needed to better understand the specific mechanisms by which Flavokawain modulates cell migration and its potential applications in cancer therapy.

Lunasin is found in soy, legumes, and some cereal grains, known for its potential anti-inflammatory, antitumor, and antimetastatic properties (45). Although there is limited information on its role in modulating cell migration, some studies have explored its effects on cancer cells. In breast cancer, Lunasin has been shown to suppress the migration and invasion of breast cancer cells by inhibiting matrix metalloproteinase-2/-9 (MMP-2/-9) via the FAK/Akt/ERK and NF-κB signaling pathways (45). This implies that Lunasin may compete with integrins in order to bind with the extracellular matrix (ECM), consequently suppressing the integrin-mediated signaling pathway. In colon cancer, Lunasin has been found to inhibit metastasis by interacting with α5β1 integrin, inhibiting FAK/ERK/NF-B signaling, and enhancing the ability of oxaliplatin to stop metastases from spreading (177). The objective of this study was to examine the impact of peptides derived from soybean protein β-conglycinin on the motility of peripheral polymorphonuclear leukocytes in humans. The findings of the study demonstrated that the peptides MITLAIPVNKPGR and MIT elicited the migration of polymorphonuclear leukocytes via a mechanism that is dependent on FPR1. The migration process was impeded by the presence of tert-butoxycarbonyl (Boc)-MLP, which is an inhibitor of FPR. Additionally, prior treatment with pertussis toxin (PTX) also hindered the migration. The research findings indicated the identification of chemotactic peptides for human polymorphonuclear leukocytes, which were derived from endogenous enzyme digests of soybean protein (173).

Numerous bioactive cationic peptides (BCPs) have demonstrated the ability to impede cellular migration in breast cancer cells. As an example, the administration of PR39 exhibited notable suppression of invasion and migration in 4T1 cells, potentially working in conjunction with Stat3 siRNA to effectively hinder cellular proliferation and migration. The P44/42 MAP kinase protein, which is essential for the migration of breast cancer cells, was found to be negatively regulated by the peptides FR8P and FR11P Furthermore, it was observed that the compound MAP-04-03 displayed significant inhibitory properties on cellular migration when administered at a concentration of 5 μM. Specifically, it was able to inhibit approximately 40% of cell migration, as determined by an IC50 value of 61.5 Mm (17, 174).

In summary, the intricate interplay between bioactive peptides and cell migration offers an interesting area of study with potential implications for advancing our understanding of cancer progression and treatment.