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Cancer remains a formidable global health challenge, characterized by alarmingly high incidence and mortality rates. Traditional clinical therapies are often accompanied by obvious toxicity and side effects, highlighting the urgent need to develop safer and more effective therapeutic alternatives. In recent years, polysaccharides have emerged as promising candidates for anti-tumor drugs due to their wide sources, high biocompatibility and low toxicity. This review summarizes recent advances in anti-tumor effects of polysaccharides, covering their underlying mechanisms, key signaling pathways and selective toxicity characteristics. Polysaccharides exert synergistic anti-cancer effects through multi-target, multi-pathway mechanisms, including the induction of immune cell polarization and tumor cell apoptosis, inhibition of tumor cell migration and angiogenesis, and modulation of key signaling pathways such as P53, NF-κB, and Wnt/β-catenin. Among these, polysaccharides with specific monosaccharide compositions, optimal molecular weights, β-glycosidic linkages, triple-helix conformations, or those that are chemically modified, exhibit enhanced biological and anti-tumor activities. Future efforts should focus on elucidating structure-activity relationships, developing targeted delivery systems to improve bioavailability and tumor specificity, and advancing large-scale, multi-center, long-term clinical trials to support the development of safe and effective polysaccharide-based anti-cancer therapeutics.
1 IntroductionCancer is a major global health problem as it has the highest incidence and mortality rates (1, 2). There are several available options for treatment, including surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy (3). These treatment options do not fully remove the tumors and negatively affect the quality of life for the patients (4). Therefore, finding high-efficacy, low-toxicity anti-cancer drugs along the lines of the existing treatment options is a valued pursuit.
Polysaccharides, have attracted growing interest due to their wide availability, low cost, and high safety profile (5, 6). These high molecular weight (MW) compounds are composed of multiple saccharide units joined together by glycosidic bonds, and are present in plants, fungi, algae, and microorganisms (7) (Figure 1). As unique natural products, polysaccharides offer several advantages that surpass those of traditional therapeutic drugs. While numerous natural products-including flavonoids, alkaloids, terpenoids, and quinones-exhibit anti-tumor activity, polysaccharides are distinguished by their unique physicochemical properties and multifaceted biological actions. Crucially, unlike cytotoxic small-molecule drugs that indiscriminately target proliferating cells, polysaccharides operate primarily through immunomodulation-engaging multiple immune checkpoints and effector pathways-while concurrently exerting selective cytotoxicity against malignant cells and sparing normal tissues. This dual functionality-potent anti-tumor efficacy coupled with low systemic toxicity and exceptional biocompatibility-directly addresses the dose-limiting toxicity that severely constrains the clinical utility of traditional chemotherapy. Bibliometric analysis of the past two decades reveals a marked increase in publications centered on keywords such as “polysaccharides,” “anti-cancer mechanism,” and “chemotherapeutics,” underscoring escalating scientific interest and the need for a comprehensive synthesis of accumulated evidence. Despite this wealth of data, a cohesive, evidence-based synthesis integrating mechanistic insights, structure-activity relationships, natural sources, selectivity profiles, and translational progress remain absent. This review addresses this critical gap by critically synthesizing current preclinical and clinical evidence, emphasizing how structural features-molecular weight, glycosidic linkages, monosaccharide composition, spatial conformation, chemical modifications-dictate biological function and therapeutic efficacy. By systematically evaluating the cumulative evidence, this work provides a rigorous foundation to guide rational drug development and accelerate clinical translation. Importantly, although other natural and synthetic compounds demonstrate anti-cancer potential, polysaccharides hold exceptional promise-not merely as adjunctive agents, but as viable alternatives to conventional therapies-owing to their tumor-selective action, favorable safety margin, and capacity to restore endogenous anti-tumor immunity.
Sources of polysaccharides. Polysaccharides derived from plants, fungi, marine algae, and microorganisms exert anticancer effects through six primary mechanisms: growth inhibition, apoptosis induction, immunomodulation, NO pathway activation, metastasis suppression, and metabolic regulation, et al. (Draw using figshare: https://www.figdraw.com/. The authorized ID: IRAPI09f3f).
This review aims to advance the understanding of polysaccharides’ anti-tumor action, their metabolic pathways, their clinical applications, and the current limitations hindering translation from theory to practice. This serves as a foundation for developing viable polysaccharide-based anti-cancer treatments.
2 The therapeutic mechanism of polysaccharides on cancer(Table 1)Polysaccharides exert anti-tumor effects through multiple interrelated mechanisms, including immune regulation, inhibition of proliferation, induction of apoptosis, activation of the nitric oxide (NO) pathway, and suppression of migration and angiogenesis. These mechanisms collectively contribute to their extensive anti-cancer activity.
MechanismPolysaccharidesRegulatory pathwayActivity immunityRefRegulation of Immune CellsPueraria root polysaccharidesMacrophages (RAW 264.7, M2 to M1 phenotype), dendritic cells, natural killer cells, T cell, B cell.T-cytotoxic cells and B-cell NK, IL-4, IFN-y and TNF-γ↑; macrophage proliferation, NO↑(8–10)Polygonatum Sibiricum polysaccharide (PSP)MacrophagesCD86+, M1 phenotype↑; CD206+, M2 phenotype↓(11)Radix Bupleuri polysaccharideT cellCD4+ T cell, MAPK and NF-κB signaling pathways↑(12)Bacterial exopolysaccharidesT cell, natural killer cells, dendritic cellsTh1 T cells, IL-12, TNF-α↑(13)Fungal polysaccharidesMacrophages, T cellM1 polarization, CD40, CD80, CD86, MHC-II, CD44+, CD62L+, TCF1+↑; TIM-3 and CD317↓(14, 15)Ginsenoside polysaccharidesT cell, B cell.Thymus and spleen weight, IL-10, TNF-α, IL-6, PI3K/AKT signaling pathway↑(16)Pectic polysaccharide PEP-1MacrophagesM1 phenotype, phosphorylation of NF-κB and MAPK↑; M2 phenotype↓(17)Inhibition of Cancer Cell ProliferationPhosphorylated fucoidan-natural product, Sulfated galactanG2/M, G0/G1 phase arrest and apoptosisCyclin-dependent kinase inhibitor p21, p53↑; epithelial-mesenchymal transition, cyclin-D, cyclin-E, cdk-4, cdk-2, EGFR↓(18–20)Hedyotis diffusa polysaccharideG0/G1 phase arrestCaspase-3, -8, and -9↑; Bcl-2↓(21)Safflower polysaccharideG0/G1 phase arrestBax, cleaved caspase-3↑; Bcl-2, COX-2↓(22)Promotion of Cancer Cell ApoptosisAlgal polysaccharides (Homogeneous sulfated polysaccharide SHA1P-2, sulfated alginate polysaccharide TGC161, fucoidan, etc.)T cell proliferation, promotes the apoptosis of tumor-associated macrophages,Phosphorylated IRF3,Polysaccharides regulate immune cells to anti-cancer.
Note: ↑ indicates increase/promotion/activation, while ↓ indicates inhibition/reduction/inactivation.
2.1 Regulate the immune cellsPolysaccharides primarily combat tumors by enhancing immune function rather than direct cytotoxicity (45–47). They reverse the immunosuppressive tumor microenvironment by activating various immune cells, including macrophages, dendritic cells, NK cells, and T lymphocytes (48, 49) (Figure 2). For example, polysaccharides from Pueraria root stimulate the activate macrophages (RAW 264.7), dendritic cells, NK cells, T and B lymphocytes, and cytokine secretion. This consequently leads to the inhibition of the progression of tumors by acting on multiple mechanisms (8, 50). For instance, yeast-derived β-glucan has been reported to enhance the cytotoxic activity of natural killer (NK) cells against breast cancer cells in both 2D and 3D culture systems (9). Specifically, polysaccharides modulate macrophage polarization (10).
Dynamic changes in the tumor microenvironment. The dynamic interplay of immune cells (including T cells, dendritic cells, macrophages, and B cells) in the tumor microenvironment, highlighting antigen presentation, IFN-γ signaling, and the induction of tumor cell apoptosis via the caspase cascade. (Draw using biorender: https://www.biorender.com/).
Polygonatum Sibiricum polysaccharide (PSP) mediated the TLR4/MyD88 pathway resulting in M2-to-M1 repolarization as shown by the increase in CD86+ cells, decrease in CD206+ cells, and the consequent anti-hepatoma effect (11). Radix Bupleuri polysaccharide (RBP) contains neutral (RBP-1) and acidic (RBP-2, RBP-3) fractions. Acidic components show stronger macrophage activation. RBP-3 binds TLR2/4, activates MAPK and NF-κB pathways, and alleviates immunosuppression by modulating CD4+ T cell differentiation (12). Bacterial exopolysaccharide (EPS) enhances Th1 immunity in colorectal cancer (CRC) models by binding TLR2 on dendritic cells in a MyD88-dependent manner, inducing IL-12 and TNF-α secretion, which promotes T cell-mediated tumor killing (13). Lentinus edodes Polysaccharide (LEP) enhances CAR-T cell efficacy in solid tumors by promoting a central memory phenotype (CD44+, CD62L+, TCF1+) and reducing exhaustion markers (TIM-3, CD317) (14). In addition, a study from the United States demonstrated that lentinan modulates gut microbiota composition, increasing the abundance of beneficial bacteria such as Lactobacillus and Bifidobacterium, which in turn enhances systemic anti-tumor immune responses and suppresses colorectal cancer growth in murine models (15). It also repolarizes TAMs to M1 and amplifies ferroptosis via the “IFN-γ-ferroptosis-ROS-Caspase-3 axis”. Combined with iron ions in nano-delivery systems, LEP enhances Fenton-like reactions and remodels the tumor microenvironment (51). LEP also regulates multiple pathways (PI3K/Akt, Wnt/β-catenin, AKT/Nur77/Bcl-2) (52), and immune functions, demonstrating broad anti-cancer potential (53).
Other polysaccharides also exhibit immunomodulatory effects. Fungal heteropolysaccharide TOP60–1 binds TLR2/4, promotes M1 polarization (upregulating CD40+, CD80+, CD86+, MHC-II), and inhibits tumor migration through direct and immunomodulatory mechanism (54). Similarly, polysaccharides isolated from the medicinal fungus Inonotus obliquus (Chaga) have been shown to act as agonists for TLR2 and TLR4 on macrophages, stimulating the secretion of NO, TNF-α, and IL-6, thereby inhibiting cancer cell growth in vitro and in vivo (16). Ginseng polysaccharides (GPS) ameliorates immune organ weight, modulates cytokines (IL-10, TNF-α, IL-6), and enhances PI3K/AKT signaling in S180 sarcoma mice, achieving a 66.52% tumor inhibition rate after 10-day oral administration (17). Lonicera japonica Thunb polysaccharide delivered via exosomes enhances dendritic cell function and strengthens CD8+ T cell responses, offering a novel anti-cancer strategy (55). Pectic polysaccharide PEP-1 induces M2-to-M1 transition via NF-κB and MAPK phosphorylation, promoting apoptosis of Hepa1–6 cells in vitro and in vivo (56).
2.2 Inhibit cancer cell proliferationPolysaccharides inhibit tumor growth by inducing cell cycle arrest at various phases (G0/G1, S, or G2/M), thereby suppressing uncontrolled proliferation (57). For example, a phosphorylated fucoidan-natural product complex upregulates p21, induces G2/M arrest and apoptosis, and suppresses epithelial-mesenchymal transition in oral cancer cells in a dose and time dependent manner (58). Combined with gemcitabine, it synergistically enhances apoptosis and cell cycle arrest in sarcoma models (59). A Hedyotis diffusa polysaccharide induces G0/G1 arrest in Hep2 cells, activates caspases-3, -8, and -9, and downregulates Bcl-2, triggering apoptosis (60). In another study, a polysaccharide from Pleurotus ostreatus upregulates Caspase-9 and Bax, modulates P53, cyclin D, and Cdk4, and induces G0/G1 arrest in Ehrlich ascites carcinoma cells (18). A sulfated galactan isolated from the marine fungus G. fisheri inhibits EGFR/ERK signaling, downregulates cyclin-D, cyclin-E, cdk-4, and cdk-2, and upregulates P53 and p21, leading to G0/G1 arrest in cholangiocarcinoma (19). In addition, a carboxymethylated derivative of laminaran from the brown alga Saccharina cichorioides exhibited potent anti-proliferative and anti-invasive activities against human melanoma SK-MEL-28 and colon cancer DLD-1 cells in three-dimensional (3D) cell culture models, highlighting the importance of chemical modification and advanced culture systems for evaluating polysaccharide bioactivity (9). Furthermore, the Safflower polysaccharide significantly reduces Bcl-2 and COX-2, increases Bax and cleaved caspase-3, and induces G0/G1 arrest in tongue squamous cell carcinoma, inhibiting tumor growth in vitro and in vivo (21).
2.3 Promote cancer cell apoptosisApoptosis is an autonomous, genetically controlled and ordered cell death process that maintains internal stability (33) (20). Polysaccharides trigger apoptosis-a programmed, genetically controlled cell death-through both intrinsic (mitochondrial) and extrinsic (death receptor) pathways, contributing to their anti-tumor efficacy (22).
HK@PPP-BDBA nanoparticles derived from Physalis peruviana polysaccharide induce ROS generation and promote apoptosis in MCF-7 and HeLa cells, while promoting apoptosis cells, resins increasing maturity and anti-tumor immunity (61). Acetylated Dendrobium huoshanense polysaccharide activates both mitochondrial and Fas/FasL pathways in HCT116 cells (62). Ganoderma lucidum polysaccharides (GLP), is an acid polysaccharide composed of glucose, mannose, galactose, xylose, fructose and arabic (63). GLP selectively prevents pancreatic cell survival, inhibits phage migration through ROS and induces mitochondria death (64). The biological activities of polysaccharides extracted by different methods also change, NaCl-extracted GLP enhances splenocyte proliferation and cytokine secretion, while hot water-extracted GLP promotes B-cell activation (65). Nanoparticles based on Peach gum polysaccharide (PGP) induce mitochondrial apoptosis (Bax, Bcl-2, cytochrome C release) and repolarize macrophages to M1 phenotype, reversing immunosuppression (66). A nanoparticle system constructed from Lycium barbarum polysaccharide (LBP) and triptolide significantly reduce mitochondrial membrane potential, increase ROS, and induce efficient apoptosis with low toxicity (67). A homogeneous polysaccharide, IRPS-TE-3 (68) and Poria cocos polysaccharide (34) demonstrate anti-apoptotic and immunoprotective activities in non-tumor contexts. Fucoidan activates macrophages via 4-1BB targeting and TNF signaling. This activation indirectly induces apoptosis and G1 arrest in pancreatic cancer cells (69).
Marine algal polysaccharides (MAP) exhibit diverse pro-apoptotic mechanisms (70, 71). A sulfated polysaccharide isolated from the red seaweed Gracilaria cornea by a Brazilian research group was shown to induce mitochondrial apoptosis in MCF-7 breast cancer cells through ROS-mediated activation of caspase-9 and caspase-3, while exhibiting low toxicity to normal fibroblasts (72). In breast cancer (BC) cell, MAP induce mitochondrial apoptosis via ROS elevation, lipid peroxidation, and caspase-9/3 activation (23). A water-soluble MAP extracted from Sargassum by Digala et al. was shown to induce specific cell death in HeLa cells of cervical cancer (CC), which selectively induces apoptosis in HeLa cells with minimal toxicity to normal cells (24). A homogeneous sulfated polysaccharide, SHA1P-2, promotes TAM apoptosis via CD206-ERK-ROS axis and suppresses T-cell proliferation (25). The sulfated alginate polysaccharide TGC161 inhibits STING-TBK1-IRF3 pathway, reduces T-cell apoptosis, and enhances anti-tumor immunity (26).
A sulfated polysaccharide from the green alga Caulerpa cupressoides inhibits melanoma migration and colony formation without inducing apoptosis (27). The anti-tumor mechanism against lung cancer (LC) is more complex. MAP reprogram transcriptome to induce apoptosis and cell cycle arrest in LC cells (28). In contrast, silver nanoparticles synthesized from MAP of fine specula exhibited strong cytotoxicity against A549 cells, while normal cytotoxicity was relatively low (29). On the contrary, porphyria from red algae enhances immune surveillance through indirect anti-tumor effects (30).
2.4 Activate the nitric oxide pathwayNO plays a dual role in tumor biology: at high concentrations, it directly induces cancer cell, and it also regulates angiogenesis and immune responses. Polysaccharides often activate macrophages to upregulate inducible NO synthase (iNOS), producing NO that contributes to tumor suppression (31, 32).
For example, although Astragalus Polysaccharides (APS) itself has limited direct inhibitory effects on MCF-7 BC cells, conditioned medium from APS-treated RAW264.7 macrophages significantly inhibits cancer cell proliferation (inhibition rate of 41%) and induces G1 phase arrest. Further studies indicate that APS upregulates the expression of NO and TNF-α in macrophages, while also modulating the expression of apoptosis-related genes in cancer cells-upregulating the pro-apoptotic protein Bax and downregulating the anti-apoptotic protein Bcl-2, resulting in a significantly increased Bax/Bcl-2 ratio and initiation of apoptosis (73). Similarly, the GLP (molecular weight 14942 Da) isolated from Colombian radioactive mushrooms not only enhances macrophage proliferation and phagocytosis but also induces the secretion of NO, iNOS, and various cytokines (such as TNF-α, IL-1β, IL-6, and IL-10), thereby exerting synergistic anti-tumor effects (74). The Grifola frondosa polysaccharide (GFP) and GLP, have been confirmed as ideal biological response modifiers that enhance both specific and non-specific immune functions. GFP activates the macrophage system and increases NK cell activity, potentially inhibiting tumors through the release of effector molecules like NO (35). GLP mainly regulates immune cells such as macrophages, thereby improving the host immune microenvironment. This regulation indirectly affects the tumor microenvironment. NO may be a key mediator of its anti-tumor mechanism (36).
In addition to immune regulation, NO can also directly induce apoptosis of cancer cells through the mitochondrial pathway. For instance, a novel polysaccharide SPS extracted from Sargassum fususiforme can induce apoptosis in human LC A549 cells, accompanied by the loss of mitochondrial membrane potential and the accumulation of reactive oxygen species (ROS). Western blot analysis showed that SPS treatment upregulated the expression of P53 and Bax, down-regulated the expression of Bcl-2, activated caspase-9 and caspase-3, and led to PARP cleavage. This indicates that polysaccharides may activate the caspase cascade by triggering the production of NO or related cellular stress, inducing mitochondrial membrane permeability and the release of cytochrome c, thereby achieving anti-tumor effects (37).
2.5 Inhibit cancer cell migrationCancer cell migration and invasion are key drivers of metastasis and treatment failure. Polysaccharides from diverse sources suppress these processes through multiple mechanisms, targeting adhesion molecules, matrix metalloproteinases (MMPs), and signaling pathways (75).
Polysaccharides from diverse sources share a common ability to suppress cancer cell migration, as demonstrated in multiple experimental systems. Li et al., using in vivo, in vitro, and in silico analyses, showed that kiwi fruit polysaccharide inhibits migration and invasion of human gastric AGS cells, reduces tumor volume, and remodels the immune microenvironment by downregulating PD-1 and M2 markers while promoting M1 macrophage polarization (38). Capparis ovata polysaccharide suppresses viability and migration of CRC cells (Caco-2, HT-29) by downregulating VEGF and GSK-3β (76). More recently, acidic polysaccharide-enriched extracts from the same sea cucumber species were shown to inhibit the migration and invasion of triple-negative breast cancer cells by upregulating E-cadherin and downregulating MMP-7 and MMP-9, further supporting the anti-metastatic potential of marine-derived polysaccharides (77).
A water-soluble GLP suppresses LC cell viability and migration by reducing phosphorylation of ERK1/2, FAK, AKT, and Smad2, and inducing degradation of TGF-β and EGF receptors, thereby reducing metastatic nodules (39). Among citrus peel polysaccharides, HBE-II most strongly inhibits migration of triple-negative BC cells and angiogenesis by downregulating MMP-9 (78). Laminarin from brown algae inhibits pancreatic cancer cell migration via mitochondrial membrane depolarization, disrupted calcium homeostasis, and suppressed ROS signaling, while showing synergy with 5-fluorouracil (5-FU) (40). Collectively, polysaccharides exert anti-metastatic effects through cell cycle regulation, apoptosis induction, migration/invasion suppression, and immune modulation (41). Sulfated galactomannans, especially low-molecular-weight derivatives, induce G1 arrest, apoptosis, and significantly suppress migration in A549 cells (79).
2.6 Inhibit tumor angiogenesisTherefore, inhibiting tumor angiogenesis has become an important anti-cancer strategy, aiming to “starve” tumors, block metastasis routes, improve immune cell infiltration, and enhance chemotherapy sensitivity. Polysaccharides inhibit tumor angiogenesis through multiple mechanism (80–84). For instance, Liu et al. reported that sulfated polysaccharides from brown algae competitively inhibited VEGF-VEGFR2 binding and blocked ERK and Akt signaling (85). Ren et al. further demonstrated that Dandelion polysaccharides down-regulate HIF-1α through PI3K/AKT, reducing the expression of VEGF in the LC model (86). Additionally, citrus peel polysaccharide directly inhibit endothelial tube formation (78). Beyond direct actions on endothelial cells, polysaccharides can indirectly suppress angiogenesis through immunomodulation (87). Fucoidan downregulates VEGF and modulates M2 macrophage polarization (42). Sea cucumber polysaccharide Ht2 suppresses MMP-2/MMP-9, impairing ECM remodeling and angiogenic conditioning (77). Furthermore, a medicinal mushroom heteropolysaccharide simultaneously targets TLR-4 and VEGF, combining immune activation with angiogenesis inhibition (43). LEP elevates IFN-γ and suppresses angiogenesis independently of T-cells (88). A polysaccharide extracted from the roots of Polygala tenuifolia also reduces EGFR, VEGF, and CD34 expression in OC models (44).
In conclusion, polysaccharides exert anti-tumor effects primarily through immunomodulation, via an intricate network of interconnected cellular and molecular mechanisms. These encompass the activation of immune cells (particularly macrophage M1 repolarization and T cell-mediated responses), induction of tumor cell cycle arrest, triggering of apoptotic cascades via mitochondrial and death receptor pathways, elicitation of NO-dependent cytotoxicity, inhibition of migration and invasion, and suppression of angiogenesis. Their multi-targeted, synergistic modes of action, alongside excellent biocompatibility, render polysaccharides highly promising candidates for both monotherapy and combination anti-cancer therapy (Figure 3).
The influence of immune cells on the tumor microenvironment. The antigen-presenting cells activate T cells, while anti-PD-1 therapy blocks PD-1/PD-L1 suppression, enabling T cells, NK cells, and other immune cells to inhibit tumor growth, proliferation, and migration. (Draw using figshare: https://www.figdraw.com/. The authorized ID: UPWTS8969f).
3 Polysaccharides modulate tumor metabolism through key signaling pathways(Table 2, Figure 4)Polysaccharides exert anti-tumor effects not only through direct immunomodulation and induction of apoptosis (as detailed in Section 2) but also by interfering with the metabolic reprogramming of cancer cells. Tumor cells exhibit altered metabolism, such as enhanced glycolysis (Warburg effect), increased glutamine consumption, and elevated lipid synthesis-to support uncontrolled proliferation. Emerging evidence indicates that polysaccharides modulate multiple signaling pathways, including P53, NF-κB, Wnt/β-catenin, PI3K/Akt, TLR, and Fas/FasL-ROS/JNK-that are intimately linked to these metabolic processes. This section highlights how polysaccharides, through these pathways, reshape tumor metabolism to suppress proliferation, induce cell death, and enhance anti-tumor immunity.
SourceNameMonosaccharide compositionCancerMechanism.Ref.Astragalus membranaceusAstragalus Polysaccharides (APS)Glucose, rhamnose, xylose, mannose, glucuronic acid, arabinose, and galactoseLung cancer cells (LC, A549, NCI-H358),
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