Natural products (NPs) are highly structurally diversified, ubiquitous life forms and derivatives of living organisms and minerals. They have been used extensively, especially in traditional medicine, to manage diverse diseases [1]. They have also contributed immensely to drug discovery in making current conventional drugs, serving as a direct source of medicinal substances, raw materials in drug production, lead compound design prototypes, and taxonomic biomarkers for new drug search and discovery [2]. NPs are associated with prominent, apparent beneficial properties [3] (as shown in Table 1) against conventional drugs or radiotherapy (as implicated in cancer management), including minimal side effects, toxicity, allergenicity, and low-cost isolation, identification, characterization, and production.

Synthetic drugs, including antibiotics used in aquaculture, primarily aim to prevent infection, leading to fatalities of “aquatic products” with correspondingly low productivity. However, their irrational use undermines the purpose. Although used optimally, it does not guarantee a clean bill of zero health risks to humans [4]. These drugs, including chloramphenicol, sulfamethazine, oxytetracycline, and furazolidone, remain residues in aquatic animals, with their bioaccumulation and biomagnification linked to human carcinogenicity ^[5][6][7][5,6,7]. Cancer is a leading cause of death globally, with yearly increasing cases [8] and an estimated 19 and 10 million new occurrences and deaths, respectively, in 2020 [9]. The risk/predisposing factors impact the DNA repair system following mutation in a single cell [10]. The pioneer single precancer cell produces many neoplastic cells and tissues via specific mechanisms, leading to undesirable physiological states of the cell, the surrounding cells, tissues, and the entire system. Clinically managing or controlling cancer cells often involves using single and multiple chemotherapeutic drugs to kill or destroy benign or malignant tumor cells and applying radiation to target sites ^[11][12][11,12]. Chemotherapy usually consists of administering high doses of synthetic chemicals for extended durations. Thus, the chemotherapeutic management of cancer has obvious negative implications. Most notable are the drop in the quality/standard of living of most recipient patients due to the extensive side effects of chemotherapeutic drugs on the surrounding cells and systems, the cost of acquiring and maintaining the therapy, and the contribution of chemicals to increasing drug resistance [10]. Radiation therapy has negative implications, including bioaccumulation of radiation, inadequate replacement of damaged stem cells, and injury [13].

NPs are also being exploited to produce anti-infective agents, especially with emerging infectious diseases, antibiotic resistance, and the dearth of new chemotherapeutic agents. Furthermore, the importance of NPs with immunomodulatory and antioxidant properties in combating bioterrorism cannot be overemphasized. The inadequacies in current therapeutic options highlight the need for safer, cheaper, and cost-effective alternative therapies, mainly from various natural products (NPs) that are abundant in the environment. One awakening mindset involves using marine probiotics for their inherent enormous potential [3]. Marine probiotics are a group of natural microbial dwellers of the marine ecosystem that, through their biological activities, apparently contribute to improving aquatic life forms through disease resistance, growth, stress tolerance, reproduction, and water quality ^[14][15][14,15]. They are being exploited for possible utilization in disease prevention and management and have many genera and species belonging to different phyla, including Pseudoalteromonas spp. The cold-adapted Pseudoalteromonas spp. are diverse understudied marine probiotics usually resident in the extreme marine environment and has shown great potential for therapeutic and biotechnological applications [16].

S/N	Therapy	Side Effects	Therapy Cost	Production Cost	Drug Resistance	Bioaccumulation	Mutation	Injury	Reference
1	Chemotherapeutic drugs	Extensive side effects	High cost of acquiring and maintaining therapy	High cost of development and production of candidate drugs	Contribution of chemicals to increasing drug resistance	Bioaccumulation of chemicals	Not applicable	Not applicable	[17][19]
2	Radiation	Extensive side effects	High cost of acquiring and maintaining therapy	Not applicable	Not Applicable	Bioaccumulation of radiation	Induction of mutation	Inadequate replacement of damaged stem cells	[13]
3	Natural products	Minimal side effects	Relatively low cost of acquiring and maintaining therapy	Relatively low cost of isolation, identification, characterization, and production	Little or no contribution to resistance	Little or no accumulation	No induction of mutation	No injuries	[18][20]

2. Probiotics, Sources, and Classifications

Probiotics resulting from the Greek words “Pro bios,” which translates to “for life” ^[19][21], are a class of microorganisms, including bacteria, viruses (such as bacteriophages), and fungi (yeast and mold) that can be ingested or topically applied for dietary and numerous medicinal (physiological and immunological) purposes ^[8][20][21][8,22,23]. Examples include Bifidobacterium, Streptococcus, Bacillus, Escherichia coli, Lactobacillus, Saccharomyces, Coccobacilli, and Propionibacterium and are in varying classifications, mechanisms of action, and corresponding functions. They preserve specific qualities, including, but not limited to, the ability to inhibit pathogens in the gut, navigate and survive via intestinal transit and gastric/bile secretions, adhere to the mucosa of the intestine, have immunomodulating and other biological effects ^[10][22][10,24]. Probiotic strains should be thoroughly characterized, safe for the intended application, backed by at least one successful human clinical trial per generally accepted scientific criteria, and alive in adequate numbers in the product at the time of usage ^[23][25]. Other considerations in choosing for medicinal purposes include non-toxicity, non-pathogenicity, beneficial effects, and appreciable shelf life. Probiotics have been applied in managing diverse medical conditions [10]. Also, several preclinical and clinical trials have suggested potent therapeutic applications. Probiotics are traditionally used and present in fermented food products (e.g., milk, yogurt, cheese, buttermilk, kombucha, sauerkraut, and tempeh) and supplements [10]. The major classifications of probiotics include lactic acid (e.g., Streptococcus, Lactobacillus, Enterococcus, and Bifidobacterium) and non-lactic acid strains (e.g., Bacillus, Clostridium, and Propionibacterium), yeasts (e.g., Saccharomyces, Candida, and Debaryomyces) and viruses, with each group exhibiting different mode of operation ^[24][26]. Based on ecosystems, terrestrial and aquatic or marine-based probiotics are the classifications ^[25][27]. Probiotics are involved in the production of inhibitory substances which prevent the adhesion of pathogens to the intestinal epithelium, direct inhibition of gram-negative bacteria, regulation of short-chain fatty acids, downregulation of proinflammatory cytokines, colonization of intestinal permeability, regulation of electrolyte adsorption, maintenance of the immune response of the intestine, and maintenance of lipid metabolism ^[24][26].

3. Marine Probiotics and General Therapeutic Potentials

Marine probiotics abound in the aquatic ecosystems. Indigenous and exogenous microbiota from aquatic animals is the primary source for isolating probiotic strains, with the Lactobacilli, Pseudomonas, Shewanella, Fluorescens, Phaeobacter, and Bifidobacteria being the most common genera ^[26][27][28,29]. They have many beneficial roles, including the protection of aquatic life forms. They naturally act as disease control agents in aquatic plants and fishes, promote growth, improve digestion and immune systems, provide sources of nutrients, improve water quality, encourage reproduction, form beneficial relationships with the host and the environment, enhance gut health and immune response in higher animals, and improve human health by preventing and treating various diseases such as cancer, gastrointestinal disorders, respiratory infections, and skin diseases ^[19][28][29][21,30,31]. They also engage in the blockage of the pathogen’s ability to utilize certain nutrients, prevention of their attachment to the host environment, distortion of the enzymatic activities of the pathogens, enhancement of the quality of water, stimulation of the immune system, and improvement of host nutrition. Marine probiotics are a promising source of novel bioactive compounds with anticancer, antibacterial, immunomodulatory, antioxidant, anti-inflammatory, and antiviral properties, as have been implicated in several studies ^{[25][30][31][32][33][34][35][36][37]}[27,32,33,34,35,36,37,38,39]. Studies have detailed the potential of yeast as a probiotic for cancer management ^[38][40], especially the isolates from marine ecosystems ^{[39][40][41][42][43]}[41,42,43,44,45] and floras of the gut system ^[40][42]. Various marine yeast microbiota genera with potential anticancer effects have been identified, including Saccharomyces, the most studied genera, particularly in colorectal cancer, as discussed by Sambrani et al. ^[38][40]. Others are Candida, Debaryomyces, Kluyveromyces, Pichia, Saccharomyces, Cryptococcus, Rhodosporidium, Rhodotorula, Sporobolomyces, Mrakiafrigida, Guehomyces pullulans, Rhodotorula, Rhodosporidium, Yarrowialipolytica, Aureobasidium, Metschnikowia spp., Torulopsis spp., Pichia, Kluyveromyces, Williopsis, Pseudozyma spp., Hansenula, Trichosporon, Filobasidium, Leucosporidium, Mrakiafrigida, Guehomyces pullulans, Metschnikowia, Rhodotorula, Cystobasidium, and Yamadazyma ^[43][44][45,46]. The lactic acid bacteria (LAB) genera and species, including Lactobacillus (L. casei, L. acidophilus, L. fermentum, L. delbrueckii, L. helveticus, L. paracasei, L. pentosus, L. plantarum, L. salivarius, L. rhamnosus GG, L. johnsonii), Bifidobacterium (B. bifidum, B. longum, B. lactis, B. infantis, B. breve, B. adolescentis), Leuconostoc spp. (Ln. lactis, Ln. mesenteroidessubsp. Cremoris, Ln. mesenteroides subsp. dextranicum), and Streptococcus spp. (S. salivarius subsp. thermophilus) are highly diversified and studied probiotic bacteria implicated in the inhibition and apoptosis of various human cancer cells ^{[30][45][46][47]}[32,47,48,49]. Other reported bacterial probionts include Bacillus (B. fermenticus, B. subtilis), Clostridium butyricum, Enterococcus faecium, Pediococcus pentosaceus, Lactococcus lactis, Propionibacterium, and Streptococcus thermophilus ^[47][49]. Actinomycetes such as Streptomyces and Micromonosporaceae are also promising candidates. Trioxacarcins A–C, anthraquinone, Macrodiolide tartrolon D, and Streptokordin obtained from Streptomyces spp. exhibited significant antitumor/cytotoxic activities against various cancer cell lines ^[48][49][50][50,51,52]. Although limited information is available on cancer management among marine probiotics, few probiotics are known to possess anticancer properties through several mechanisms (Figure 1), primarily due to meta-biotics, which consist of structural components, metabolites, and signaling molecules with specific chemical structures as shown in Enterococcus lactis IW5 ^[51][52][53][53,54,55]. These components optimize various physiological functions of the host, including regulatory, metabolic, and behavioral reactions. Marine probiotics, such as Lactobacilli and Bifidobacteria, modify the mucosa by increasing the production of chemokines and host defense peptides, inducing dendritic cell maturation, and increasing cell proliferation and apoptosis ^[49][51]. Marine probiotics can modulate cancer by inducing apoptosis, inhibiting mutagenic activity, downregulating oncogene expression, inducing autophagy, inhibiting kinases, reactivating tumor suppressors, preventing metastasis, and producing meta-biotics, as already shown in B. animalis, B. infantis, B. bifidum, L. paracasei, L. acidophilus, and L. plantarum I-UL4 against MFC7 cancer cells ^[51][52][53,54]. Although probiotics alone may not suffice in treating cancer, they can mitigate colorectal cancer (CRC) by enhancing the efficacy of treatments and acting on the immune system ^[54][56]. Studies have shown that probiotic strains, specifically lactic acid bacteria mixtures, can differentially induce and modulate macrophage pro- and anti-inflammatory cytokines and phagocytosis ^[51][53]. It also can mitigate the effects of DMH-induced colon shortening and positively affect leukocyte count and colon tumor growth ^[54][56]. The combinations also induce the excretion of proinflammatory IL-18 by tumor cells and are crucial in mitigating CRC ^[54][56]. Probiotics generally exhibit antitumor activities by enhancing the intestinal microbiota, degrading possible carcinogens, and modulating gut-associated and systemic immune responses ^[55][57]. Worthy of mention is that several anticancer drugs of marine origin are in clinical use with sufficient approvals, including cytarabine, vidarabine, nelarabine, fludarabine phosphate, trabectedin, eribulin mesylate, brentuximab vedotin, polatuzumabvedotin, enfortumabvedotin, belantamabmafodotin, plitidepsin, lurbinectedin, bryostatins, discodermolide, eleutherobin, and sarcodictyin ^[39][56][41,58]. With the increasing popularity of antibiotic stewardship, the misuse and abuse of antimicrobials in developed and developing countries have remained high, with an attendant increase in the development of bacterial resistance. Especially with its forecasted implications ^[57][59], possible avenues for developing newer antimicrobials must be exploited. Marine probiotics are a potential source of antimicrobial substances. Pereira et al. ^[57][59] showed that marine-isolated L. lactis and E. faecium produce effective bacteriocin antibiotics ^[57][59]. The bacteriocin-producing potential of Lactococcus spp. also agrees with Sarika et al.’s study ^[58][60]. Other marine probiotics that can produce antibacterial substances have continued to emerge. Pseudoalteromonas spp. and Vibrio spp. produced antibacterial substances with activity comparable to established antibiotics ^[59][61]. Marine lactic acid bacteria of the genera Lactococcus spp., Enterococcus spp., Lactobacillus spp., and Leuconostoc spp. have been reported to produce antimicrobial substances against Vibrio spp. and Photobacterium spp. ^[60][62]. Kaktchan et al. ^[61][63] revealed that Lactococcus spp., cultured in an earthen pond, could produce a bacteriocin-like substance that inhibits the growth of Vibrio spp. and Pseudomonas aeruginosa. Immune system arsenals generally recognize viral antigens, preventing their multiplication within the host ^[62][64]. However, research should remain proactive, as infective agents constantly change and could sprout newer pathogenic strains. Although the exact mechanisms of action are still unclear, some probiotics have shown a solid ability to prevent viral multiplication in fish and can be used as antiviral agents. Lactobacillus spp. and B. subtilis boosted viral resistance by preventing viral infections in Paralychthus olivaceus and grouper fish, respectively ^[63][64][65,66]. The production of antiviral compounds by Pseudoalteromonas spp. has protected Prawns and Sea breams against viral pathogens ^[65][67]. Other studies have also shown the possibility and potential of deploying probiotics in the marine environment as agents to prevent viral infections ^[66][67][68,69]. A robust immune system correlates well with defense against infections and diseases. Studies on the immune-enhancing potential of marine probiotics have shown promising results ^[31][35][33,37]. Wasana et al. ^[45][47] reported the expression of the immunomodulatory genes in zebrafish larvae exposed to a novel Pseudoalteromonas xiamenensis, a marine probiotic that induced the down-regulation of proinflammatory cytokine genes. In another study, a significant reduction in the levels of proinflammatory cytokines was observed in CRC patients who received six viable probiotics of Lactobacillus and Bifidobacterium strains ^[68][70]. The propensity of reactive oxygen and reactive nitrogen species as free radicals to alter the body’s proteins, lipids, and DNA is a significant cause of some human diseases ^[69][71]. Due to synthetic antioxidants’ toxic effects ^[70][72], marine probiotics have been studied as a natural source of antioxidants. In a study, Alsharmmari et al. ^[71][73] espoused the novel marine probiotic, Enterococcus durans, which possesses an efficient antioxidant potential. Other studies that corroborated and supported the possible use of marine probiotics as potential sources of antioxidants are those by Husain et al. ^[71][73] and Angulo et al. ^[72][74]. Representative marine probiotic-derived drugs and their microbial sources are presented in Table 2. Therapeutic potentials of marine probiotics are illustrated in Figure 2.