Prospects and challenges of novel natural marine-derived compounds in melanoma treatment

Abstract

The increasing incidence of melanoma poses significant challenges for conventional treatment approaches, plagued by drug resistance and adverse side effects. Natural marine-derived compounds have gained prominence in melanoma research for their unique bioactivities and diversity. This review delves into the therapeutic potential of these compounds in melanoma treatment, emphasizing their distinctive advantages such as multi-target mechanisms and immune modulation, which distinguish them from traditional therapies. Additionally, we discuss the challenges in translating these agents into clinical applications, including formulation stability, bioavailability, and regulatory hurdles. Recent advancements in preclinical models such as organoids and completed clinical trials further support the exploration of marine-derived compounds in melanoma management. By consolidating current research, this review underscores the potential of these agents to enhance treatment efficacy and foster new therapeutic strategies.

Key Words: Melanoma; Natural marine-derived compounds; Therapeutic applications; Traditional therapies; Clinical translation

Core Tip: Marine populations represent reservoirs of novel bioactive metabolites with diverse groups of chemical structures. Marine-derived compounds offer promising therapeutic avenues for melanoma by targeting multiple pathways involved in tumor growth, metastasis, and immune regulation. This review delineates the antitumor mechanisms of these therapies and evaluates their efficacy and safety in comparison to traditional treatment modalities. It also highlights emerging strategies for clinical translation, particularly the integration of patient-derived organoid models for preclinical validation. Leveraging these advanced models may bridge the gap between in vitro research and clinical application, facilitating the development of personalized, multimodal melanoma therapies.

INTRODUCTION

The global incidence of melanoma, a malignant tumor originating from melanocytes, has greatly increased, largely due to increased ultraviolet exposure[1]. Clinically, it presents major challenges due to its rapid progression, strong metastatic capacity, and resistance to conventional treatments. Over the past few years, the therapeutic landscape for advanced melanoma has undergone a profound paradigm shift. The introduction of immune checkpoint inhibitors (ICIs) [e.g., anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 and anti-cytotoxic-T-lymphocyte-associated antigen 4], rapidly accelerated fibrosarcoma B-type (BRAF)/mitogen-activated extracellular signal-regulated kinase-targeted therapies, therapeutic vaccines, small-molecule inhibitors, and rationally designed combination regimens has dramatically improved patient outcomes and extended survival in selected populations[2,3]. However, many patients still experience resistance, relapse, or suboptimal responses, underscoring the need for novel therapeutic strategies[4].

The efficacy of traditional treatments such as surgery, chemotherapy, and radiotherapy face is significantly limited. Surgical options are less viable in metastatic patients, whereas chemotherapeutic agents often result in systemic toxicity and low response rates[5]. Additionally, the selection of drug-resistant clones and tumour heterogeneity further erode treatment durability[6]. In response, marine-derived natural products have attracted increasing interest because of their unique bioactivities and chemical diversity. Compounds isolated from algae, sponges, and marine fungi are capable of inhibiting tumor proliferation, inducing apoptosis, and modulating immune responses[7]. Their multitarget mechanisms offer opportunities to surmount conventional resistance pathways and enhance existing regimens.

This review outlines the therapeutic potential of marine-derived compounds in melanoma treatment, highlighting their mechanisms, advantages over traditional agents, and translational challenges.

SOURCES, CLASSIFICATION, AND BIOLOGICAL ACTIVITY OF NATURAL MARINE DERIVATIVES

Marine organisms—including algae, sponges, corals, mollusks, and microorganisms—represent an unparalleled reservoir of structurally diverse bioactive compounds with therapeutic potential. These compounds are typically classified into alkaloids, terpenoids, polyketides, peptides, and polysaccharides, each contributing unique mechanisms relevant to anticancer activities[8-10].

The sources and classification

Marine macro-organisms, such as sponges, tunicates, corals, and macroalgae (e.g., brown and red algae), have yielded a wide range of metabolites including alkaloids, terpenoids, polysaccharides, and phenolic compounds, many of which exhibit notable antitumor, antioxidant, and immunomodulatory activities[11-14]. Marine microorganisms, particularly fungi and bacteria, also contribute numerous secondary metabolites with anticancer and antimicrobial potential[15,16]. The novel chlorinated metabolite chlovalicin B (1) was isolated from the marine basidiomycete Digitatispora marina, which was obtained from driftwood collected at Vannøya, Norway. This compound at a concentration of 50 μmol/L demonstrated weak cytotoxic activity against the human melanoma cell line A2058, resulting in approximately 50% cell viability[17]. Collectively, the extreme and diverse conditions of marine ecosystems drive the evolution of unique chemical structures, making marine biodiversity a promising reservoir for anticancer drug discovery[18].

Medicinal potential

Marine-derived compounds exhibit structural features distinct from terrestrial natural products, which may confer novel mechanisms of action and therapeutic selectivity.

Antitumor effects: Certain marine-derived compounds exhibit significant antitumor activity, effectively inhibiting the proliferation of cancer cells and inducing apoptosis. For example, extracts from marine algae and sponges have shown efficacy in preclinical melanoma models by disrupting oncogenic signaling pathways. These mechanisms include modulation of cell cycle regulators, promotion of apoptosis, and inhibition of angiogenesis. Marine-derived peptides, for example, have been found to impair cellular homeostasis, leading to increased apoptosis and reduced tumor growth[18,19]. In addition, marine alkaloids and terpenoids are known to block enzymes essential for tumor progression, further supporting their therapeutic relevance[20,21].

The regulatory roles of noncoding RNAs (ncRNAs) in cancer have gained attention, and some marine-derived agents have been shown to modulate ncRNAs that influence tumor growth and apoptosis, indicating a promising therapeutic pathway[22]. The structural diversity of marine compounds also enables simultaneous modulation of multiple signaling pathways, which may help overcome resistance commonly seen in melanoma therapy[23-26]. Recent studies support these findings. Akazamicin and Actinofuranone C, two aromatic compounds from the deep-sea bacterium Nonomuraea sp. strain AKA32, showed strong cytotoxicity in B16 melanoma cells (IC₅₀: 1.7 μmol/L and 1.2 μmol/L, respectively), while N-formylanthranilic acid displayed moderate activity (IC₅₀: 25 μmol/L)[27]. These findings provide further evidence of the structural diversity and bioactivity of marine natural products, particularly in the context of melanoma.

Anti-inflammatory and immune regulation: Research on marine-derived substances has increasingly underscored their anti-inflammatory and immune-regulating properties, thereby highlighting their promising potential for therapeutic applications in a variety of inflammatory diseases. For example, fucoidan Chordaria flagelliformis derived from the alga Chordaria flagelliformis enhanced innate immune activity via CD11c integrins in mice, increasing the cytotoxicity of splenic mononuclear cells against B16 melanoma cells by 1.9-fold[28]. Polysaccharides from marine algae, such as ulvans, demonstrate significant anti-inflammatory properties by modulating various signaling pathways associated with the inflammatory response[29]. Furthermore, peptides and alkaloids derived from marine organisms have been recognized as potent inhibitors of inflammatory mediators, highlighting their potential as natural alternatives to conventional anti-inflammatory medications[30]. These compounds exhibit their effects through a variety of mechanisms: They inhibit proinflammatory cytokines such as tumour necrosis factor alpha and interleukins, while simultaneously promoting the secretion of anti-inflammatory cytokines[31]. They also influence immune cell behavior, particularly by polarizing macrophages towards an anti-inflammatory phenotype-a process crucial for resolving inflammation and facilitating tissue repair[32]. The structural diversity of marine bioactive underpins this broad range of mechanisms, reinforcing their value as promising drug candidates for treating inflammatory diseases.

Furthermore, the therapeutic potential of marine-derived substances extends beyond inflammation reduction; these compounds also play a significant role in modulating immune system activity. For example, some marine polysaccharides can enhance the activity of immune cells such as macrophages and natural killer (NK) cells, helping the body defend against infections and disease[33]. This immunomodulatory effect is especially important in autoimmune disorders, where immune imbalance causes ongoing inflammation and tissue damage. By restoring immune homeostasis, marine-derived compounds may offer novel strategies for addressing these conditions[34].

Development and application challenges

Despite their therapeutic potential, marine-derived products face challenges in extraction, sustainability, and clinical translation. The complex biochemistry of marine organisms requires advanced techniques to isolate active compounds with minimal degradation. Traditional methods like solvent extraction are often inefficient, while newer approaches such as ultrasound-assisted and enzymatic extraction improve yield and compound stability[24]. Principles of green chemistry are increasingly applied to reduce environmental impact[35]. Sustainable harvesting is essential to prevent ecological disruption. Regulatory frameworks, including national permitting systems and international agreements like the Convention on Biological Diversity, help ensure ethical and equitable access to marine resources[19,36].

Meanwhile, emerging technologies such as genomics, metabolomics, and co-culturing strategies are accelerating the discovery of novel bioactive compounds by activating previously silent biosynthetic pathways[37]. Overcoming these technological and regulatory hurdles is vital for advancing marine natural products toward clinical application.

ANTITUMOR EFFECTS OF NATURAL MARINE-DERIVED COMPOUNDS ON MELANOMA

Natural marine-derived compounds possess the ability to target multiple pathways involved in tumor growth, proliferation, and metastasis, rendering them promising candidates for developing novel therapeutic agents against melanoma[38,39]. The unique chemical structures and mechanisms of action of marine natural products provide a valuable source of potential leads for drug discovery, highlighting the importance of continued exploration of marine biodiversity for combating cancer[40,41].

Antiproliferative effects

Various marine-derived compounds have significant effects on the proliferation of melanoma cells. For example, fucan A is a fucose-containing sulfated polysaccharide extracted from brown seaweed Spatoglossum schröederi. Notably, fucan A has demonstrated promising efficacy in inhibiting the growth of triple wild-type melanoma cell lines by approximately 57%-a result comparable to cisplatin, but without toxic effects on normal melanocytes[38]. Other sulfated fucans from marine sources, such as FucSulf1 and FucSulf2, also show 30%-50% inhibition of melanoma cell proliferation[42]. Seriniquinone, another marine natural product, displays strong cytotoxicity and selectivity against melanoma cells by modulating key signaling pathways related to proliferation[43]. Likewise, Nortopsentins and their derivatives have shown anti-proliferative activity across multiple human cancer cell lines, including melanoma, suggesting their potential as broad-spectrum anticancer agents[39]. Furthermore, 1-O-alkylglycerols have been reported to inhibit cell proliferation in melanoma cell lines[44].

In melanoma cells, the metabolism of marine derivatives often leads to cell cycle arrest, particularly at the G1/S and G2/M phases. For example, certain compounds derived from marine sources have been demonstrated to upregulate the expression of cell cycle inhibitors such as p21 and p53. This mechanism effectively prevents cells from advancing into the S phase, thereby reducing cellular proliferation[45]. They also activate apoptosis-related genes such as Bax and caspase-3, promoting programmed cell death[46]. By modulating cell cycle progression and apoptotic signaling in tandem, these agents selectively inhibit tumor growth. This action is associated with increased doubling time and cell cycle arrest, reinforcing their potential as targeted therapeutics.

Modulation of the cell cycle and apoptosis-related gene expression

Regulatory mechanisms governing the melanoma cell cycle: Regulation of the cell cycle is essential for the control of cell proliferation, and natural marine derivatives have demonstrated potential in modulating these processes within melanoma cells. Compounds such as heteronemin have been shown to induce cell cycle arrest by modulating the expression of cyclins and cyclin-dependent kinases, which are crucial for the progression of the cell cycle[46]. These compounds may inhibit melanoma cell proliferation by altering the levels of key regulatory proteins, including cyclin D1 and p21. For example, fucoxanthin has been reported to block the G1 phase of the cell cycle in melanoma cells, thereby reducing proliferation[47,48]. By targeting these regulators, marine derivatives effectively slow tumor growth, and this effect may enhance the response of melanoma cells to chemotherapeutic agents, thus improving treatment outcomes.

Regulation of gene expression in apoptosis: Apoptosis, also known as programmed cell death, represents a vital mechanism for the elimination of cancer cells. Marine derivatives have been demonstrated to induce apoptosis in melanoma cells by upregulating the expression of genes associated with apoptosis, including Bax and caspase-3. For example, heteronemin activates apoptotic signaling by increasing the production of reactive oxygen species (ROS), which leads to higher rates of apoptosis in melanoma cells[49]. Similarly, diphlorethohydroxycarmalol (DPHC) has been found to upregulate pro-apoptotic proteins while downregulating anti-apoptotic factors, thereby enhancing apoptotic activity in melanoma cells[50]. This combined mechanism-not only promoting cell death but also reducing survival signaling-helps lower tumor cell viability. As a result, marine-derived compounds may improve the overall effectiveness of combination therapies.

Antimetastatic characteristics

In addition to their antiproliferative and proapoptotic effects, natural compounds derived from marine sources have demonstrated promising antimetastatic properties in melanoma. Research has demonstrated that specific marine polysaccharides can inhibit the migratory and invasive properties of melanoma cells, thereby effectively preventing metastasis[51]. For example, fucan A not only inhibited the proliferation of melanoma cells but also significantly diminished vascular mimicry, a process closely associated with angiogenesis and metastasis[38]. Other compounds, such as psammaplin A, have been reported to disrupt key signaling pathways involved in cell movement and invasion, further supporting their role as potential antimetastatic agents[52]. By acting on multiple fronts-suppressing both tumor growth and metastatic spread-these marine-derived compounds offer a comprehensive therapeutic strategy for melanoma management.

REGULATION OF KEY SIGNALING PATHWAYS BY NATURAL MARINE DERIVATIVES IN MELANOMA

Role of natural marine derivatives in the phosphoinositide 3-kinase/protein kinase B signaling pathway in melanoma

The phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway is integral to cellular survival, growth, and metabolism, thereby establishing itself as a critical target in the treatment of melanoma. Natural marine derivatives, particularly those obtained from the marine fungus Aspergillus clavatus, have exhibited significant inhibitory effects on this pathway[49]. For example, extracts from Aspergillus clavatus suppressed PI3K/Akt activation, leading to decreased proliferation and increased apoptosis. Similarly, the marine carotenoid fucoxanthin downregulates genes such as IRS1, EIF4B, and ELK1, thereby inhibiting the PI3K/Akt pathway and inducing both cell cycle arrest and apoptosis[53]. Spatane diterpenoids from the brown algae Stoechospermum marginatum also block this pathway and have demonstrated in vivo antitumor effects in mice bearing B16F10 melanoma, with no significant toxicity[54]. Together, these findings support the potential of marine compounds as PI3K/Akt inhibitors for melanoma therapy.

Functions of natural marine derivatives in the mitogen-activated protein kinases signaling pathway in melanoma

The mitogen-activated protein kinases (MAPK) signaling pathway represents another essential mechanism involved in the progression and metastasis of melanoma. Natural marine compounds are known to exert substantial effects on this pathway, thereby influencing the behavior of melanoma cells. Hot water extract of Endarachne binghamiae extract has been shown to significantly inhibit the activation of MAPK signaling pathways in RAW 264.7 cells stimulated with lipopolysaccharide, which subsequently leads to a reduction in the expression of proinflammatory cytokines[55]. Compounds like DPHC can also downregulate components of the MAPK pathway, leading to reduced melanogenesis and proliferation in melanoma cells[50]. These effects highlight the potential of marine derivatives to influence MAPK signaling and disrupt melanoma development.

Impact of marine derivatives on signaling pathways

The diversity of natural marine derivatives offers distinct advantages in the modulation of cellular signaling pathways. The influence of marine-derived compounds transcends individual pathways, as they frequently demonstrate a multifaceted impact on diverse signaling cascades. These compounds can concurrently regulate multiple signaling pathways, including the PI3K/Akt and MAPK pathways. This interaction generates a synergistic effect that enhances their therapeutic efficacy. For example, marine polyphenols have been shown to modulate the expression of critical proteins involved in both the PI3K/Akt pathway and the MAPK pathway, resulting in comprehensive alterations in melanoma cell behavior. Marine derivatives can directly influence the activation of the PI3K/Akt and MAPK signaling pathways[56]. In addition to these major pathways, marine derivatives have also been shown to influence other important signaling networks such as nuclear factor-kappa B (NF-κB). Bioactive components from seaweed extracts, for example, can reduce pro-inflammatory cytokine production by suppressing NF-κB activity, thereby helping to control inflammation in the melanoma microenvironment[56]. This ability to target multiple, interconnected pathways highlights the complexity of melanoma biology, and supports the use of marine-derived compounds in combination therapies aimed at improving treatment outcomes.

COMPARISON WITH TRADITIONAL TREATMENTS FOR MELANOMA

Conventional melanoma therapies, including chemotherapy (e.g., dacarbazine) and BRAF inhibitors, often show initial efficacy but are limited by drug resistance and significant side effects[3,57]. Dacarbazine achieves low objective response rates (ORRs) (15%-20%) with limited survival benefit, while BRAF inhibitors, despite higher initial ORRs (50%-70%), frequently encounter rapid resistance through alternative pathway activation[58-60]. In contrast, marine-derived compounds such as eribulin, irinotecan, and cabozantinib exhibit multi-target mechanisms-including apoptosis induction, microtubule disruption, and immune modulation-offering advantages in overcoming resistance and enhancing treatment tolerability[61-65]. Eribulin, for example, achieves ORRs up to 40% in refractory melanoma, significantly outperforming dacarbazine[42,61]. Similarly, curcumin demonstrates efficacy (ORRs: 30%-50%) in drug-resistant patients, with favorable tolerability[21,66].

Safety profiles and tolerability

Comparative studies highlight that marine-derived agents not only provide comparable or superior efficacy to traditional therapies but also exhibit lower toxicity. Agents like irinotecan and trastuzumab show reduced systemic side effects compared to chemotherapies, which are often associated with myelosuppression, alopecia, and gastrointestinal toxicity[21,48,66,67]. Specifically, marine drugs demonstrate lower neutropenia rates (approximately 10%) vs conventional agents (30%-50%), improving treatment adherence and patient quality of life[61].

Resistance mechanisms and reversal potential

Resistance to conventional therapies arises from drug efflux, target mutations, and tumor microenvironment adaptation[68-70]. Marine-derived compounds, including eribulin and curbatitin, effectively counter these mechanisms by downregulating P-glycoprotein, inhibiting proliferation, and modulating survival pathways, thereby restoring drug sensitivity[71-73]. Their multi-target nature provides a strategic advantage in addressing the complex, adaptive behavior of melanoma cells[68]. While preclinical evidence suggests that marine-derived compounds may overcome drug resistance and improve treatment tolerability, it is essential to assess their clinical performance in melanoma patients. Several marine-derived agents have progressed to early-phase clinical trials, offering preliminary insights into their therapeutic potential and safety profiles.

Clinical evidence of marine-derived compounds in melanoma

In addition to their preclinical efficacy, several marine-derived compounds have advanced into clinical trials for melanoma treatment, as summarized in Table 1[74-90]. Plitidepsin, sourced from the tunicate Aplidium albicans, has undergone both monotherapy and combination therapy trials. It showed limited efficacy as monotherapy (ORR: 5.7%, median overall survival: 3.5 months) but demonstrated improved responses when combined with dacarbazine (ORR: 21.4%, SD: 32.1%)[74,75]. Similarly, Bryostatin 1, derived from the marine bryozoan Bugula neritina, has been evaluated in both monotherapy and combination therapy settings. As monotherapy across several phase I and II trials, Bryostatin 1 demonstrated modest clinical activity[76] in metastatic melanoma, with stable disease (SD) rates ranging from 5.6% to 21%, and limited objective responses (partial response (PR)/complete response: 0%-2%)[77-81]. Notably, when combined with temsirolimus, a mammalian target of rapamycin inhibitor, in a phase I study (NCT00112476), Bryostatin 1 achieved a higher PR rate of 12% and an SD rate of 52%, suggesting synergistic effects in the combination setting[89]. These findings, akin to Plitidepsin, reinforce the potential advantages of combination regimens over monotherapy for marine-derived compounds in melanoma treatment. Other marine-derived agents such as Kahalalide F, Marizomib, and Trabectedin have also been evaluated in early-phase trials for melanoma. While these compounds exhibited disease stabilization in some patients, their overall response rates remained low, and most studies were limited by small sample sizes and heterogeneous patient populations, often including multiple solid tumor types[82-84,90].

Table 1 Completed clinical trials of marine-derived compounds in melanoma treatment.

Compound name	Source organism	NCT number and Ref.	Phase	Patient population	Methods	Total/melanoma	Clinical efficacy	Most frequent grade 3+ treatment-related adverse events
Eribulin	Marine sponge (Halichondria okadai)	I	Advanced solid tumors (including melanoma)	Monotherapy	40/2	-	Neutropenia: 9/38 (24%); fatigue: 4/38 (11%); peripheral neuropathy: 3/38 (8%)
Plitidepsin (Aplidin®)	Marine tunicate (Aplidium albicans)	II	Advanced malignant melanoma	Monotherapy	39/39	PR/CR: 2/35 (5.7%); SD: 5/35 (14.3%); median OS: 3.5 months	Myalgia: 3/35 (8.6%); injection site reaction: 2/35 (5.7%); hypersensitivity: 1/35 (2.9%); hypotension: 1/35 (2.9%)
		I-II	Advanced malignant melanoma	Combination (with dacarbazine)	I: 28/28, II: 38/38	I: PR/CR: 3/19 (15.8%); SD: 4/19 (21%); II: PR/CR: 6/28 (21.4%); SD: 9/28 (32.1%)	ALT elevation: 10/36 (28%); fatigue; nausea/vomiting; hypersensitivity; creatine phosphokinase elevation
Kahalalide F	Marine mollusk (Elysia rufescens)	II	Advanced malignant melanoma	Monotherapy	24/24	PR/CR: 0/24 (0%); SD: 5/21 (24%); median OS: 10.8 months	Transaminase elevation (AST/ALT): 14/24 (58%); gamma-glutamyl transferase: 2/24 (8%); lymphopenia: 2/24 (8%)
		I	Advanced solid tumors (including melanoma)	Monotherapy	38/5	PR/CR: 1/5 (20%)	Transaminase elevation (AST/ALT); hypokalemia; hypoglycemia
Salinosporamide A (Marizomib)	Marine actinomycete (Salinispora tropica)	NCT00667082, Millward et al[90]	I	Advanced solid tumors (including melanoma)	Combination (with vorinostat)	22/17	PR/CR: 0/17 (0%); SD: 11/17 (64.7%)	Fatigue: 4/22 (18%); nausea: 5/22 (23%); vomiting: 4/22 (18%); diarrhea: 2/22 (9%); deep vein thrombosis: 3/22 (14%); thrombocytopenia (grade 4): 1/22 (5%)
Didemnin B	Marine tunicate (Trididemnum solidum)	II	Metastatic melanoma	Monotherapy	14/14	PR/CR: 0/14 (0%)	Hypersensitivity reactions; nausea, vomiting, diarrhea
		II	Advanced malignant melanoma	Monotherapy	19/19	PR: 1/19 (5.3%); SD: 7/19 (36.8%)	Anaphylactoid reactions: 7/19 (37%); severe myopathy: 1/19 (5%)
Bryostatin 1	Marine bryozoan (Bugula neritina)	NCT00006022	Ia/Ib	Metastatic melanoma	Monotherapy	17/-
		NCT00112476, Plimack et al[89]	I	Advanced or metastatic solid tumors (including melanoma)	Combination (with temsirolimus)	30/-	PR: 3/25 (12%); SD: 13/25 (52%);	Neutropenia (10%); thrombosis (10%); creatinine elevation
		II	Metastatic melanoma	Monotherapy	34/34	SD: 7/34 (21%)	Myalgia: 6/34 (18%); lethargy
		II	Metastatic melanoma	Monotherapy	16/16	SD: 1/15 (6.7%); median survival: 134 days	Myalgia: 6/16 (37.5%); nausea/vomiting: 1/16 (6.25%)
		I	Advanced solid tumors (including melanoma)	Monotherapy	19/-		Myalgia: 3/3 (100%) at highest dose (65 µg/m²); cellulitis/phlebitis
		I	Advanced malignancies (including melanoma)	Monotherapy	35/2	PR/CR: 2/2 (100%)	Myalgia: 4/11 (36%); headache: 5/11 (45%); phlebitis: 11/23 (48%); acute infusion reactions (dyspnea, flushing, hypotension, bradycardia): 6/35 (17%)
		II	Metastatic melanoma	Monotherapy	49/49	PR/CR: 1/49 (2%)	Myalgia: > 90%; nausea/vomiting: 6/49 (12%)
		II	Metastatic melanoma	Monotherapy	18/18	SD: 1/18 (5.6%)	Myalgia: 1/18 (5.6%)
Dolastatin-10	Marine mollusk (Dolabella auricularia)	II	Metastatic melanoma	Monotherapy	12/12	Objective response rate: 0/12 (0%)	Neutropenia: 4/12 (33%)
Trabectedin (Yondelis®)	Marine tunicate a (Ecteinascidia turbinat)	I	Advanced solid tumors (including melanoma)	Monotherapy	72/2	PR/CR: 1/2 (50%)	Neutropenia: 15/72 (20%); elevated transaminases: 40/103 cycles (39%); fatigue: 14/72 (19%)

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CR: Complete response; OS: Overall survival; PR: Partial response; SD: Stable disease.

Collectively, these clinical findings highlight the potential of marine-derived compounds in combination therapies, while also pointing to the urgent need for larger, melanoma-specific phase III trials to confirm these early results. Due to small sample sizes and heterogeneous trial designs, caution should be taken when applying these findings to broader clinical practice. SD rates reported across multiple studies support the potential of these agents to help control disease progression. However, frequent grade ≥ 3 treatment-related adverse events-such as fatigue, elevated liver enzymes, and hematologic toxicity-were also noted. These outcomes reflect both the promise and limitations of current marine-derived therapies, and underscore the importance of further clinical refinement, particularly in dosing strategies and patient selection.

FUTURE PERSPECTIVES

Marine-derived compounds hold significant promise for melanoma therapy by offering direct antitumor effects and overcoming drug resistance. Certain marine polysaccharides can modulate immune responses and enhance therapeutic outcomes in melanoma patients[64]. However, realizing their full clinical potential requires addressing several research gaps.

Discovery and optimization of novel marine-derived compounds

While marine biodiversity offers a vast reservoir of bioactive molecules, much of it remains underexplored. Recent discoveries highlight marine metabolites targeting apoptosis regulators like Bcl-2 and Survivin[91]. High-throughput screening and microbial co-cultivation techniques, which activate silent biosynthetic gene clusters, have expanded chemical diversity and accelerated bioactive compound discovery[92-94]. Future efforts should focus on integrating these technologies to unlock novel antitumor agents from marine resources while ensuring sustainable bioprospecting[95,96]. In parallel, the limited natural abundance and ecological sensitivity of many marine organisms raise significant sustainability concerns. Future research should prioritize the development of sustainable harvesting strategies, microbial production systems, and biosynthetic engineering approaches to ensure scalable and environmentally responsible access to marine-derived compounds[97]. Addressing these challenges is essential to align future discovery efforts with ecological preservation and industrial feasibility.

Synergistic potential with immunotherapy

Although ICIs have revolutionized melanoma treatment, resistance remains a major obstacle[49,98,99]. Marine-derived compounds, such as sulfated polysaccharides and eckol, exhibit immunomodulatory properties that enhance T-cell activation, NK cell function, and dendritic cell maturation[59,64,100]. These attributes suggest potential synergy with ICIs, offering avenues to boost immune responses and mitigate resistance. Despite promising preclinical data, clinical validation of marine compounds in combination with ICIs remains limited and warrants further investigation[101].

Integration of advanced technologies in marine drug development

The integration of advanced technologies and personalized medicine is critical for translating marine-derived compounds into clinical applications. Tools such as biomarker discovery, functional genomics, and high-resolution imaging enhance the prediction of therapeutic responses and elucidate disease mechanisms, supporting safer and more effective drug development. Safety and efficacy assessments remain fundamental in this process. Marine-derived agents, particularly those from marine microorganisms, exhibit promising anticancer and dermatological activities-such as 2,4,6-triphenyl-1-hexene from Bacillus sp. APmarine135, which demonstrates strong anti-melanogenic effects[101]. However, comprehensive toxicological evaluations, including pharmacokinetics, bioavailability, and dose-limiting toxicities, are essential to confirm their safety profiles. Despite their generally low systemic toxicity, many marine compounds still lack clinical validation, highlighting the need for rigorous preclinical evaluation. Emerging technologies like gene editing (e.g., CRISPR-Cas9) and nanotechnology offer opportunities to enhance the delivery efficiency, target specificity, and therapeutic efficacy of marine compounds. Nanoparticle-based carriers can improve bioavailability and reduce systemic toxicity by delivering marine agents directly to tumor sites[102]. Yet, the application of these technologies in marine drug development remains limited, requiring further exploration to optimize their integration. Simultaneously, the rise of personalized medicine, driven by multi-omics analyses and artificial intelligence, facilitates patient stratification and biomarker identification[103]. Incorporating marine-derived compounds into personalized treatment regimens demands a deeper understanding of their molecular mechanisms and biomarker associations. Preclinical models, such as patient-derived organoid (PDO) and xenografts, offer physiologically relevant platforms to validate these compounds and refine therapeutic strategies. Together, these advances underscore the importance of interdisciplinary collaboration and patient-centered approaches to ensure the safe and effective clinical translation of marine-derived compounds for melanoma therapy.

Organoid models: A promising platform for marine-derived compound validation in melanoma

Patient-derived melanoma organoid models have demonstrated the ability to recapitulate key tumor features, including cellular heterogeneity, genetic profiles, and the immune microenvironment. These advanced three-dimensional (3D) systems[104-108] have been validated as effective platforms for evaluating immunotherapies and small molecule drugs, preserving histopathological integrity and enabling assessment of immune cell interactions, such as T-cell-mediated tumor killing[109,110]. Organoids derived from diverse tumor types demonstrate clinical therapeutic responses, thereby enhancing their translational applicability[111].

The application of melanoma organoids has continued to expand, covering areas such as drug screening, immune profiling, and personalized therapy development. These models preserve both tumor-intrinsic features and immune characteristics, making them well-suited for evaluating ICIs, such as PD-1 blockade[112]. In addition to cutaneous melanoma, organoids from uveal melanoma have also been established, faithfully reflecting disease-specific biology and clinical drug responses, which further supports their use in translational studies[113]. The integration of organoid systems with microfluidic or explant-based technologies allows real-time monitoring of tumor-immune interactions and early resistance mechanisms, enabling dynamic adjustment of combination therapies based on ongoing responses[114-116]. Despite these advancements, the application of organoid models for testing marine-derived compounds in melanoma remains unexplored. Given the complex mechanisms of marine natural products, including multi-targeted effects and immune modulation, integrating these models into preclinical pipelines could offer a more physiologically relevant assessment of antitumor activity, synergistic potential with immunotherapies, and resistance mechanisms. This integration may bridge the gap between in vitro studies and clinical translation, enhancing the development of personalized, multimodal treatment strategies. To further strengthen the translational relevance of organoid models, recent innovations have greatly improved their applicability in personalized melanoma therapy. Advances in PDO technology now enable co-culture with tumor-infiltrating lymphocytes under air-liquid interface conditions, allowing functional testing of ICIs. Notably, up to 85% concordance has been observed between ex vivo organoid responses and actual clinical outcomes[117]. In metastatic subtypes such as melanoma brain metastases, scaffold-free PDOs retain key mutational signatures-including BRAF V600E, NRAS, and KIT-as well as immune architecture. This enables accurate prediction of responses to targeted therapies and real-time adaptation of treatment strategies[118,119]. Moreover, Transwell-integrated organoid-on-a-chip platforms have demonstrated the ability to distinguish between high-metastatic and low-metastatic melanoma subtypes by assessing lateral migration behavior. This facilitates early metastasis risk evaluation and patient stratification[120]. Taken together, these advanced PDO platforms offer a physiologically relevant, dynamic system for ex vivo screening of marine-derived compounds, supporting their integration into individualized melanoma treatment frameworks.

Looking forward, the incorporation of molecular profiling into therapeutic decision-making has the potential to facilitate more personalized treatment approaches for melanoma. This integration may help identify patients who are most likely to benefit from compounds derived from marine sources. This precision medicine approach aims to improve treatment efficacy and reduce toxicity through patient-specific drug selection strategies[121]. PDO platforms offer a valuable tool in this framework, as they allow compound testing in genetically and immunologically representative models. Designing tailored treatment regimens that include marine-derived agents may expand their clinical relevance and improve outcomes in melanoma management. Future research should focus on integrating melanoma organoid models into marine drug discovery pipelines to validate therapeutic efficacy, uncover mechanisms of action, and enhance translational success.

CONCLUSION

The investigation of natural marine-derived compounds for melanoma treatment represents a significant advancement in oncological therapeutics. However, it is important to acknowledge that the mechanisms of action for many of these compounds remain incompletely understood, and further investigation is required before they can be safely and effectively translated into clinical applications.

This review underscores the enhanced efficacy and reduced side effects of marine-derived agents compared to traditional therapies, particularly in patients with treatment-resistance melanoma. As our understanding of the mechanisms of action of these marine drugs deepens; and production technologies advance, there is promising potential for their clinical integration. It is imperative, from an expert standpoint, to stress the importance of a balanced interpretation of the diverse research findings on marine-derived therapies. While initial data is encouraging, conducting comprehensive clinical trials is essential to address patient response variability and the complexities of melanoma biology. The heterogeneous nature of melanoma, influenced by genetic, environmental, and immunological factors, underscores the need for thorough investigation into personalizing these marine compounds to individual patient characteristics. Moreover, the integration of marine-derived therapies into current treatment protocols requires careful consideration. Collaboration among researchers, clinicians, and pharmaceutical developers is crucial to ensure that these novel therapies complement rather than compete with established treatments. This interdisciplinary approach can help identify synergistic effects, enabling the development of more effective combination therapies to improve patient outcomes.

In summary, the potential advancements offered by marine-derived agents in melanoma treatment present a promising avenue for future research and clinical practice. By maintaining a balanced perspective that acknowledges both the potential of these compounds and the complexities of melanoma, we can pave the way for enhanced therapeutic strategies. Continued research and cooperation in this field will not only enrich our understanding of melanoma treatment but also have the potential to significantly impact patient care in the coming years.