A comprehensive search was performed using electronic databases, including PubMed, Scopus, and Web of Science. The search terms included “marine bioactive compounds,” “immunomodulation,” “marine-derived peptides,” “polysaccharides,” and “pharmacology.”

Articles were included if they met the following criteria: Published between 2010 and 2024. Focused on marine-derived bioactive compounds with demonstrated immunomodulatory effects. Provided molecular or pharmacological insights into immune pathways.

Articles were excluded if they lacked experimental data, focused solely on marine ecology, or were not written in English.

The infinite tremendous biodiversity of the marine world draws the interest of numerous scientific communities for the identification of unique biomolecules that could serve humanity in countless ways. The marine habitat, which is the source of many unknown molecules, serves as an effective energizing milieu for exploration. The discovery of any biomolecule is not merely confined to its structural elucidation; the beauty lies in the underlying function of a molecule. When considering the biological activity of these molecules, many of them are investigated for their pharmacological functions. The research progress in the marine-derived biomolecule research area provides a platform to scrutinize varied multidisciplinary fields. The probable voyage through the medicinal value of these molecules has just started with insightful and rich data that could assist and encourage an integrated interdisciplinary approach to explore and exploit these marine-derived bioactive molecules for various pharmacologically significant functions. Such unique molecules have exclusive features in their scaffolds, both in terms of organic content and structural characteristics, which make them promising chemotherapeutic agents. Biologically unique marine microorganisms, seaweeds, micro and macroalgae, mangroves, and diverse other marine animal species, which are major and indomitable parts of the ocean environment, are responsible for the synthesis and secretion of organic components of distinct origin. These conditioned marine entities continuously develop and thrive in a highly concentrated briny microenvironment, encountering many other organisms. These marine entities tend to chemically defend themselves against other antagonists by synthesizing antimicrobial secondary metabolites as a means of adapting and responding to extreme environmental conditions. This term ‘secondary metabolite’ explains their biological activity, being produced as a side metabolic consequence and not from their primary metabolic systems (Ezzat et al. 2018).

Polysaccharides

Marine polysaccharides such as fucoidans (from brown algae) and carrageenans (from red algae) have demonstrated immunomodulatory effects. Fucoidans can enhance macrophage activation, increase cytokine production, and stimulate natural killer (NK) cell activity, making them promising candidates for cancer immunotherapy (Al-Hussaniy 2022).

Peptides

Antimicrobial peptides (AMPs) derived from marine organisms like sponges, mollusks, and fish, possess dual roles in immunity by directly targeting pathogens and modulating host immune responses. For example, tachyplesins from horseshoe crabs exhibit anti-inflammatory properties by inhibiting NF-κB signaling (Fernandes et al. 2023).

Secondary metabolites

Marine-derived secondary metabolites, including alkaloids, terpenoids, and polyphenols, show diverse immunomodulatory effects. For instance, manoalide from sponges inhibits phospholipase A2, a key enzyme in inflammatory pathways, while marine alkaloids have been shown to regulate T-cell proliferation (Fernandes et al. 2023).

Bioactive compounds in marine organisms

In particular, marine algae, which include unicellular organisms known as diatoms, as well as coccoid and multicellular green, brown, and red algae, are found in diverse marine environments. Brown and red algae are the predominant marine algae and produce a wide variety of secondary metabolites that are used for defense and protection against predation and fouling. Even so, the functions of most of these metabolites have not been fully elucidated. Among marine invertebrates, sponges have attracted great interest due to their extraordinary ability to produce macrocyclic furan-containing metabolites. The brown algae, divided into three classes, include Phaeophyceae, Ectocarpophycidae, and Chrysophyceae. This biomass is rich in bioactive compounds like phenolic compounds, phycocyanins, pigments, chlorophyll, polythyristamines, saponins, mannitol, fucins, pectins, mucilages, and fatty acids such as palmitic acid, oleic acid, palmitoleic acid, linoleic acid, and sterols like squalene and sitosterol, as well as a variety of molecules like polysaccharides, flavonoids, fatty acids, and minerals, reported to possess various phytochemical and pharmacological activities. The exploitation of marine algae has developed over the immeasurable possibilities of algal bioactive compounds, including definitions such as proteins, peptides, phycobiliproteins, polyphenols, polysaccharides, sterols, fatty acids, pigments, and glycosides, with several staggering actions such as antioxidative effects, anti-inflammatory properties, neuroprotective effects, antitumor abilities, and prebiotic and synbiotic potential, as well as oral health and immune-stimulatory effects. This paper reviews the state of the art, presents information about the bioavailability of the bioactive compounds derived from marine algae, and highlights the results of published investigations that used these drugs in the early preclinical stages (He et al. 2024).

Marine animals are recognized as the ideal source of numerous promising structural templates having potent immune regulatory activities. Improvement of the foods that point out effects on the animal system and dendrimer tissues on realistic vaccinations is essential for protecting the earth (Alves et al. 2022). The immune response of the protein animals is characterized for the first time to better understand the properties of the technological route toward identifying sustainable immune modulators for development. With the advancements in technology, efficient phylogenomic tools to annotate immunity-related genes at the molecular level have been facilitated, which have proven to be beneficial. Awareness has additionally been raised about non-motile immune modulatory therapeutic agents of animal origin, which include fucoidan, among others (Anorue et al. 2023). This will probably provide massive insight into the future direction of marine immune research in animals and will support the improvement of novel marine-derived immunomodulatory therapeutics from the perspective of primary immune regulation (Kolla et al. 2023) see Fig. 1 summaries some activities of marine.

Figure 1. 

Show immune pathway of marine.

Modulation of immune responses

It is widely believed that marine bioactive compounds may contribute to broader options for the discovery and development of new and enhanced strategies for the treatment of various diseases using purified natural compounds. Marine bioactive products possess immense potential as modulators of the immune system through both direct and indirect influences on the host’s entire immune regulatory pathways, leading to the stimulation or suppression of functions such as cytokine and chemokine production, antibody formation by B cells, antigen presentation, and co-stimulation of T cells, activation and proliferation of various immune cells, including phagocytes and T cells, and the differentiation of B cells into immune plasma cells and T cells into various lineages found within the T cell family.

In implementing such regulation, marine natural compounds can thus exhibit desirable effects in a blanket fashion. Whereas immunostimulation is crucial for cancer therapy, overcoming many infectious diseases, and improving vaccines, situations where the process might be better left untriggered or differently orchestrated include cases of hyperimmune function or autoimmune conditions, allograft rejection, and chronic inflammation (Al-Hussaniy and Al-Zobaidy 2024a).

In searching for bioactive immune regulators from marine sources, many past studies have focused on lipids, carbohydrates, polyunsaturated fatty acids, depsipeptides, furanosesterterpene glycosides, linear tetrapeptides, quinones, glycolipids, guanidine alkaloids, thiazinoquinones, alkaloids, and various other isolated and defined molecular structures. Such studies have detected beneficial immunoregulatory properties such as anti-inflammatory effects, the capacity to promote or suppress ROS production from phagocytes, modulated TLR and NF-kB signaling, transcriptional influences on genes, or IFN type 1-inducing properties. Small DRPs such as bacillomycin D, brevistin, candlevins A, and arenastatin A, which are produced by particular bacterial knock-on members of marine sponges, have demonstrated immunosuppressive activities that go beyond identical functions previously observed in other DRP domains.

The main techniques employed for the isolation, purification, and characterization of marine-derived bioactive molecules are chromatography systems such as high-performance liquid chromatography and gas chromatography; spectroscopy systems such as nuclear magnetic resonance and mass spectrometry; and immunoassays. Thus, researchers use these techniques exclusively or most often, employing more than one according to the molecular traits or properties of marine components. High-performance liquid chromatography is the most commonly employed technique for isolating marine-derived compounds. These compounds remain dissolved in organic phases, and impurities are removed by the high-performance liquid chromatography system throughout the purification method due to the capacity factor, retention time, and separation factor of the analysis. These compounds are occasionally classified and frequently recognized through spectroscopy methods. For example, nuclear magnetic resonance and mass spectrometry are typically used for structural elucidation, as they characterize molecules by their reaction to electromagnetic radiation and the molecular/atomic mass, respectively, see some techniques in Fig. 2.

Figure 2. 

Shows techniques for studying marine-derived bioactive molecule.

The identification of compounds can be conducted through immunoassays, which are technologies used to detect, quantify, and/or characterize proteins using specific antibodies. This technique allows for the specific determination and quantification of bioactive molecules, demonstrating the recognition of the target.

The recognition and characterization of a marine bioactive molecule are also conducted through the biologic/pharmacologic activity of the isolated molecule. The causes and actions conducted by these compounds are investigated through pathways such as carbon metabolism, energy metabolism, replication and repair, cellular processes, and signaling. The details concerning pathways act in different manners according to the category of the study. As chemical carcinogenesis is related to anti-inflammatory potential, this association reveals the effect of marine bioactive molecules from natural sources, improving biopharmaceutical strategies for developing new drugs. In this sense, bioactive molecules present in marine animals and compounds obtained mainly from corals have been described as promising healing agents in wound healing therapy (Surwase and Thakur 2024).

Isolation and purification methods

The first prerequisite for any biological activity assessment of a bioactive molecule from a natural source is the isolation and purification from the host source. In general, bioactive molecules with immunomodulatory effects have many disadvantages such as low solubility, low expression level, poor chemical diversity, instability, and high toxicity. Therefore, the purification of the bioactive compounds of interest is of prime importance. In addition, purification of natural immunomodulatory compounds is still a challenging and difficult task due to the minute volumes present in the original crude extract and possible interference from inactive or toxic contaminants. Typically, a bioassay-guided approach is very essential for the selection of specific compounds with immunomodulatory effects within a certain pool of natural compounds. Currently, in medicinal chemistry, various advanced techniques are available to purify and characterize the research compounds, and these techniques help to identify, synthesize, and modify bioactive potential molecules of interest (Surwase and Thakur 2024).

Conventional chromatography techniques have been used for the highly time-consuming, labor-intensive, and solvent-consuming process to isolate desired bioactive molecules. These are major drawbacks, and it has an additional disadvantage that the method can result in the structural modification or degradation of the compound. In order to overcome these drawbacks, solid phase extraction, counter-current chromatography, or high-speed counter-current chromatography, and supercritical fluid chromatography proved to be fast, efficient, and a lower solvent-consuming chromatographic method that markedly enhanced and complemented the performance of other commonly used chromatography techniques in the current natural products field. These advanced chromatography techniques have good potential to separate and isolate natural products with high purity. This review also discusses advanced isolation and purification techniques including improved liquid chromatographic techniques, which aid in overcoming the limitations of conventional chromatographic methods, and further details the strong potential and scope of a wide range of diverse immune standpoint molecules present within a single compound suitable for in-depth investigation (Fernandes et al. 2023).

Structural elucidation techniques

One of the primary objectives of the isolation process is the establishment of connections between structure and activity. The elucidation of structures from the isolated natural products can be classified into two additional processes: the first would be the dereplication of all natural products from the screen, including known non-producing organisms, and the second would be the provision of complete structural characterizations of the active substances. In nearly 60% of cases, bioactivity-guided fractionation is usually employed, and only the active fraction is then subjected to full-scale isolation of its components. At the same time, the yield is usually less than 0.1%. The natural products can be classified into several categories based on their complexity.

The basic complexity can be arranged into the following ways: very simple natural products, including fragments and analogs, low molecular weight compounds, moderate molecular weight compounds, large neuropeptides and large cyclic peptides, lipopeptides, natural lipids, and xanthones, secondary metabolites, and mixtures. The general guidelines of the rudimentary structure-activity relationship can be explained by harsh lessons learned through years of unproductive isolation studies. First, the isolation steps should be combined with the maximum information to be obtained about each fraction before embarking on any structural work, and then, and only then, should fractions be isolated more productively and quickly.

In the face of the complexity of the immune system, including adjustments of pro-inflammatory and anti-inflammatory pathways, increasing interest in compounds associated with marine organisms has been growing. Several of these compounds have shown promising results in modulating the immune system. For example, from macroalgae and microalgae, a variety of sulfated polysaccharides can be obtained (Al-Hussaniy et al. 2023a). Such compounds have been described as modulators of the immune system by acting on the complement system, monocytes, macrophages, and lymphocytes, being recognized by either classical or alternative pathways. Moreover, glycolipids have also been described as important in regulating immune system cells, including modulation of acute and chronic inflammation, mainly reducing tissue edema, cell infiltration, and inhibition of pro-inflammatory cytokines. Finally, several classes of terpenoids are considered to have immunomodulatory activities, including anti-inflammatory and analgesic effects, with involvement of the NF-κB pathway (Mohan et al. 2019; Kolla et al. 2023).

Molecules obtained from marine sponges have attributes such as anti-inflammatory, antitumor, analgesic, antioxidant, antimicrobial, and anti-cancer activities (Wen et al. 2022). These compounds include terpenes, steroids, polyketides, alkaloids, purines, peptides, and macrolides, with distinct properties and are apparently able to modulate the immune response. Furthermore, compounds isolated from marine invertebrates such as echinoderms, mollusks, ascidians, and tunicates have been reported to have relevant therapeutic and diagnostic activities. These compounds include steroids, alkaloids, terpenoids, glycogen, nucleotides, peptides, and modified peptides. Additionally, metabolites from microorganisms living in association with sponges have pharmacological properties similar to those of sponges. They are generally composed of peptides and polypeptides and exhibit anticoagulant, antimicrobial, anticancer, and anti-inflammatory properties (Al-Hussaniy and Al-Zobaidy 2024b).

Antimicrobial activities

Meeting the immediate threat of infectious pathogens has been pivotal throughout evolution for host survival. Host defense processes are impaired if they have to focus on events for which delayed protection from pathogens is not granted. Originally, the first line of defense against microbes relied on direct molecular interaction between host defense proteins and conserved pathogen structures, thus providing efficient protection. This system has been employed in host-microbe interaction by diverse invertebrates and vertebrates, with the adaptive immune system of jawed animals being only superimposed on this basic innate system. Among the direct microbial elimination processes used by these organisms was the generation of natural components derived from the host itself, designed to act as membrane-disrupting molecules and to efficiently kill bacteria. This essential attribute is still conserved in more advanced species that also deploy components synthesized by either immune cells or other specialized synthetic cells in the skin and in mucosal epithelia, such as Paneth cells in the intestine (Usman et al. 2023). These cells are particularly specialized in the synthesis of secretory proteins and are known to confer powerful antimicrobial activity essential for host survival (de Sá et al. 2022).

Marine-derived peptides hold a large diversity of sequence and structural similarities with those discovered in vertebrates, retaining substantial evolutionary conservatism and biochemical significance. They represent valuable structural prototypes that were often revealed by the peculiar living conditions of the animals that release them into the surrounding environment, such as extreme temperatures, as well as the presence of specific predators and pathogens (Heo et al. 2023). In response to the selection pressures exerted by these extreme environmental conditions, which led to the evolution of extraordinary immune-defense systems, marine organisms have developed the ability to produce a wide variety of secondary metabolites which, in turn, enabled them to adapt to environmental pressures, including predator and/or pathogen antimicrobial peptides, as well as to escape their predators and/or defend themselves from bacteria, fungi, and viruses (Azhari et al. 2025). A considerable research effort has been dedicated to identifying new sources of antimicrobial activity, which, complemented with other data obtained on characterized peptides, has disclosed promising classes of marine natural products that could serve as templates for future strategy development to generate new antimicrobial agents with novel scaffolds and unique mechanisms of action (Zhang et al. 2024).

Anti-inflammatory properties

Stepwise, it appears that carrageenans reduce footpad edema by suppressing the migration of neutrophils, causing concomitant inhibition of pro-inflammatory mediators, such as cytokines and nitric oxide. Furthermore, in vivo and in vitro exposure of L. gaudichaudii extracts reduce acetic acid-induced capillary permeation, thereby blocking pro-inflammatory cytokine upregulation, leukocyte migration, and decreased nitric oxide and prostaglandin E2 levels. Additionally, Gal-1 acts as an inhibitor of carrageenan-induced cell migration and upregulation of the pro-inflammatory cytokine IL-1β, thereby functioning as a potent anti-inflammatory agent. The capacity of algal extracts to modulate inflammation is also evidenced by Halopteris scoparia. After induction of an irritative face-washing model on the mouse skin, the expression of procaspase-1, NLRP3, proteolytic fragments, and IL-1β is modulated by the presence of extract (Qiu et al. 2024). Likewise, Lactuca scabriuscula extract leads to suppression of cytokine production and inhibits the nuclear translocation of the p50 subunit, acting as a potent modulator of NF-κB. Moreover, green and brown algae revealed an anti-inflammatory ability in Caco-2 cells, as observed by the significant reduction in TNF-α/IL-8. Furthermore, the ability of Sargassum latifolium extract to diminish the recruitment of leukocytes and neutrophils during a bronchoalveolar lavage, through modulation of the cytokine levels and enhancing the activities of catalase and superoxide dismutase enzymes (Heo et al. 2023; Haki et al. 2024).

Immunomodulatory effects

Marine organisms, due to their unique habitat and relatively less explored status, are known to produce bioactive molecules that perform a variety of functions, such as structural, defense, and signaling roles. These molecules are non-immunogenic and possess several advantages over higher organisms in structural uniqueness, site specificity, and unpredictability in the design of functional molecules (Liu et al. 2022). There is an increasing demand to develop novel drugs by identifying and standardizing the bioactive molecules present in marine organisms as potential pharmacological drugs, including immune-modulatory drugs (Mohammed et al. 2021). Researchers and clinicians are placing high hopes in the use of marine-derived agents for the treatment of cancer and other degenerative diseases, for early embryogenesis, and as therapeutic agents for various skin conditions (Al-Kelaby et al. 2022; Al-Hussaniy et al. 2023a).

The immune system is a defense system, polarity, or intelligence system against foreign materials, recognizing autologous cells and tissues, and protecting from damage when decay and disease occur. Modulation of the immune system by bioactive molecules is an important area in pharmacology, derived from plant and microbial sources. Macrophages are the first line of host defense responses through the recognition of foreign materials and initiate immune responses. Macrophages are known to play a central role in site-specific tumor resistance and allograft reactions, chronic inflammation, and immune responses. Tissues of the marine environment produce multifunctional molecules, some of which have been studied for their potential immune functions (Al-Hussaniy et al. 2023b; Kolla et al. 2023).

Natural substances from a variety of sources, primarily marine, have been widely investigated for their potential to inhibit the NLRP3 inflammasome, a known contributor to various immune responses and emerging as a therapeutic target in human inflammatory diseases. Jaspamide and the cyclic depsipeptide apramides A and B from diverse marine sponges of the family Hemiasterellidae can suppress the LPS-induced upregulation of the NLRP3 protein in macrophages and its assembly and caspase-1 activity independently of potassium efflux. Another marine-derived natural product, the cyclic lipid compound spongian diterpenoid, inhibits IL-1 and IL-18 secretion in LPS-primed THP-1 cells with an IC50 of approximately 2 μM by directly targeting NLRP3. These results suggest that spongian diterpenoids could serve as immune-modulating drugs. However, because of the high toxicity of jaspamide, apramides A, and apramides B, it is unclear whether they can be used as safe and effective options for NLRP3-mediated immune disorders (Jaafar 2018; Wu et al. 2023).

NLRP3 is the binding receptor of Bacillus anthracis lethal toxin protein, a key signaling component commonly activated by both the lethal and edema factors of B. anthracis, which are the etiological agents of anthrax. Some marine sponge-derived cyclic peptides containing non-proteinogenic amino acids can inhibit B. anthracis lethal factor binding to human NLRP1 (Mohammed 2016). This suggests that these marine sources can perhaps also inhibit NLR protein-mediated immune responses. Evaluated the effect of the marine natural compound didemnins on the immune regulator lymphocyte protein tyrosine kinase and suggested that didemnin blocks the lymphocyte antigen receptor-mediated pro-B-cell upregulation of Lck and can serve as a suppressor and inhibitor of immune reactions through the non-phosphorylation of Lck in Crohn’s disease. Taken together, these studies indicate that marine natural products serve as pharmacological modulators of immune responses and that marine sources can be a fertile ground for inquiry into NLR protein function (Mohammed et al. 2020; Yu et al. 2024).

Specific examples in drug development

In recent years, researchers have focused on fish as a source of bioactive and immunomodulatory compounds (Mohammed et al. 2018). The next sections provide evidence of these activities and discuss the potential applications of the obtained molecules in the pharmaceutical industry (Jaafar and Abu-Raghif 2024). Specific examples in drug development show that fish have developed sophisticated innate immune systems with similarities to those of mammals, with conserved levels of pathogen recognition and organ compartments that perform the same functions (Mohammed and Al-Razaq 2017). The innate immune system recognizes and kills bacteria, viruses, fungi, and parasites, as well as being involved in the recovery of damaged tissues, pre-metastatic niches, tumor cells, and other microorganisms. Additionally, fish or marine-derived biomolecules represent an infinite source of bioactive compounds with novel structural scaffolds and a broad spectrum of biological activities (Elnosary et al. 2024; Azhari et al. 2025).

Outstanding reports of molecules from marine sources include bacteriocins, phycocyanins, fucoxanthin, and other pigments, fish skin gelatin, peptides from sourdough, type I antifreeze protein from ocean pout, and cod trypsin. These molecules can be used in various sectors of industry: the food function sector, as pharmaceutically active molecules, clinical therapy, cosmetics, agriculture, labware and equipment chemicals, and the environment (Rafea et al. 2020; He et al. 2024). In recent years, the pharmaceutical industry has become interested in exploiting fish mucosal surfaces as integral tools in the diagnosis, prevention, and biologic therapy of individual and collective infectious diseases of the human respiratory and gastrointestinal tracts (Abdulhamza et al. 2024). Minor constituents from mucous extracts, named fish parvalbumin, possess recognized antimicrobial activity against pathogenic organisms and have been used for biomedical and pharmaceutical applications (Al-Kuraishy et al. 2022; Hussein et al. 2023).