Nanodelivery of Traditional Chinese Medicine Monomers: An Emerging Strategy to Reprogram the Immunosuppressive Tumor Microenvironment.

Introduction
Despite significant advancements in immunotherapeutic strategies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T (CAR-T) cell therapy, Clinical outcomes remain suboptimal for cancer patients. Durable responses are predominantly observed in a subset of individuals with high tumor mutational burden, while the majority exhibit limited benefit. The presence of “cold” tumors characterized by poor immune cell infiltration substantially hinders the broader clinical applicability of ICIs.1–4 These limitations highlight the urgent need for novel approaches that can sensitize tumors to immunotherapy and mitigate associated toxicities.
Recent studies have illuminated the complex and heterogeneous nature of immune cell infiltration across different tumor types, emphasizing its critical role in determining treatment responses. Single-cell sequencing technologies have revealed that the density and composition of immune infiltrates serve as predictive biomarkers for immunotherapeutic efficacy. For instance, tumors enriched with CD8⁺ cytotoxic T lymphocytes tend to respond more favorably to ICIs, whereas those with dominant infiltration by regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are typically associated with immunosuppressive phenotypes and resistance.5 These immunological characteristics are orchestrated within the tumor microenvironment (TME), which is a highly dynamic and complex ecosystem composed of tumor cells, stromal cells, immune cells, cytokines, and extracellular matrix (ECM) components. The TME is characterized by hypoxia, acidosis, and metabolic dysregulation.6,7 Hypoxic conditions within the TME not only promote tumor cell survival and metastasis but also facilitate immune evasion by recruiting immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), TAMs, and Tregs, while concurrently upregulating immune checkpoint pathways like PD-1/PD-L1.8 In parallel, the acidic microenvironment further impairs immune cell activity and poses a physical barrier to therapeutic penetration through ECM remodeling.9
To overcome the immunosuppressive barriers of the TME, increasing attention has been directed toward the immunomodulatory potential of traditional Chinese medicine (TCM) monomers. These bioactive compounds exhibit multi-target pharmacological effects, low systemic toxicity, and favorable immunoregulatory properties. Specifically, they can also modulate cytokine profiles, enhance immune cell activation and suppress chronic inflammation.10–12 However, the clinical translation of TCM monomers is significantly hampered by inherent pharmacokinetic drawbacks, including poor aqueous solubility, low bioavailability, rapid metabolism, and insufficient tumor-specific accumulation.13–15 These challenges prevent the attainment of therapeutic concentrations at the tumor site, limiting their practical efficacy.
Nanomedicine offers a promising strategy to address these pharmacokinetic and delivery challenges. By employing passive and active targeting mechanisms, nanocarriers can enhance the stability, tumor selectivity, and controlled release of TCM monomers, thereby minimizing off-target effects.16,17 For example, pH-responsive nanoparticles can release immune-activating agents such as IL-12 within the acidic TME, effectively reconditioning the immunosuppressive milieu by reprogramming tumor-associated macrophages from an M2-like to an M1-like phenotype, thereby enhancing pro-inflammatory signaling and T cell activation.18 Moreover, multifunctional nanocarriers enable the co-delivery of chemotherapeutics and immunomodulators, enhancing antigen presentation and amplifying anti-tumor immunity.19–21 For example, a folate-modified nanosystem co-delivering doxorubicin and calcium overload inducers was shown to induce immunogenic cell death (ICD) and activate dendritic cells, thereby enhancing long-term T cell memory responses. This “kill-then-activate” synergistic antitumor strategy effectively promotes durable antitumor immunity.22
Therefore, the integration of TCM monomers with advanced nano-delivery platforms represents a transformative dual-targeting approach. This combination not only potentiates the intrinsic immunomodulatory pharmacology of TCM agents but also equips them with the capability to precisely dismantle key immunosuppressive mechanisms within the TME. This review aims to provide a comprehensive overview of the immunoregulatory roles of TAMs, MDSCs, and Tregs within the TME. We further summarize the emerging evidence on TCM monomers that target these immunosuppressive cells and discuss recent progress in nanotechnology-based delivery systems designed to improve therapeutic precision. These insights offer valuable directions for the development of TCM-based nanomedicine strategies in the context of cancer immunotherapy (Figure 1 and Table 1).

Targeting TAM with Chinese Herbal Monomer
TAMs are critical immune cells within the TME, originating from either resident tissue macrophages or bone marrow-derived monocytes.98 TAMs exhibit functional and phenotypic heterogeneity due to the complexity of the TME and the plasticity of macrophages. They are broadly categorized into two subtypes: M1 macrophages (tumor-suppressive) and M2 macrophages (tumor-promoting). M1 macrophages are activated by interferon-gamma (IFN-γ) and lipopolysaccharide (LPS), secreting pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-12, and tumor necrosis factor-alpha (TNF-α), which contribute to anti-tumor immunity.99,100 In contrast, M2 macrophages are induced by IL-4, IL-10, and IL-13, and produce anti-inflammatory mediators like IL-10, transforming growth factor-beta (TGF-β), and vascular endothelial growth factor (VEGF), facilitating tumor progression through immunosuppression and angiogenesis.101–103
TAMs exhibit bidirectional regulatory interactions, such as M1 macrophages inhibiting M2 polarization via Smad2/3 phosphorylation, while M2-derived exosomes promote M2 phenotype conversion by activating arginase-1 (Arg-1) and suppressing inducible nitric oxide synthase (iNOS) expression. Additionally, TAMs contribute to the TME by secreting cytokines like IL-6, IL-10, IL-1β, CCL18, CXCL8, and TGF-β, as well as producing angiogenic factors such as VEGF, basic fibroblast growth factor (bFGF), PDGF-β, and WNT family members. Initially, TAMs exhibit M1 polarization and exert anti-tumor effects. However, as tumors progress, they shift toward the M2 phenotype, promoting tumor cell proliferation, invasion, and metastasis through the secretion of immunosuppressive cytokines like IL-10 and TGF-β. TAMs also induce gene mutations in tumor cells via oxidative stress and nitrosation-related molecules, activating oncogenic pathways such as STAT3 and NF-κB, thereby enhancing tumor survival and proliferation (Figure 2).

Inhibition of TAM Recruitment
The CCL2/CCR2 axis plays a central role in macrophage recruitment to the TME. Disrupting this chemokine signaling pathway not only reduces monocyte infiltration but also promotes macrophage repolarization and enhances cytotoxic CD8⁺ T lymphocyte (CTL) activation, thereby improving anti-tumor immunity.104,105 Curcumin, a polyphenolic compound from turmeric, suppresses CCL2 expression in tumor cells and stromal components by inhibiting the NF-κB pathway, thereby impairing monocyte chemotaxis and limiting TAM accumulation in preclinical cancer models.51,106–108 Total glucosides of peony (TGP) inhibit TAM recruitment by targeting the NF-κB/CCL2 pathway, reducing CCL2 secretion and reshaping the tumor microenvironment.109 Targeting the CCL2/CCR2 axis with TCM monomers like curcumin and TGP presents a promising strategy to reduce the immunosuppressive TAM pool at the source. However, the clinical translation of this approach requires overcoming the complex redundancy of chemokine networks in the TME and ensuring precise spatiotemporal inhibition to avoid disrupting homeostatic immune functions.

Depletion and Inhibition of TAM
TAMs reduce immunity by activating oncogenic signaling pathways (STAT3 and MAPK) via pro-inflammatory cytokines like IL-6 and IL-1β, which promote tumor development and metastasis. Strategies targeting TAM depletion or functional inhibition show promise in enhancing tumor immune responses. Quercetin, a flavonoid from multiple traditional Chinese medicinal plants, induces TAM apoptosis by modulating Bcl-2/Bax signaling, leading to TAM reduction in the TME.110,111 Andrographolide, a diterpenoid from Andrographis paniculata, inhibits macrophage activation and cytokine production, modulating M1 and M2 phenotypes, and targeting the Wnt5a/β-catenin pathway to suppress M2 macrophage activity.112–115 Matrine, an alkaloid from Sophora flavescens, inhibits TAM activation and survival by suppressing M2 polarization and the mTOR/PI3K/Akt pathway, reducing anti-inflammatory cytokines and M2 markers without affecting M1 polarization.80,89 Resveratrol, a polyphenolic compound from Polygonum cuspidatum, exhibits dose-dependent effects on macrophage polarization, promoting M1 polarization at moderate concentrations and favoring M2 polarization at higher doses, highlighting the importance of precise dosing.90,116 Lobeline, an alkaloid from the herbal medicine lobelia, promotes polarization of TAMs toward M1-like TAMs while inhibiting their polarization toward M2-like TAMs.151 Calceolarioside B, a major compound in Akebiae Fructus, regulates M2-like TAMs polarization and infiltration to impede HCC progression by targeting MMP12.47 Directly depleting or functionally inhibiting TAMs with monomers such as quercetin and matrine offers a rapid means to alleviate TAM-mediated immunosuppression. A key challenge lies in achieving tumor-selective effects to spare resident tissue macrophages essential for normal physiology, and in carefully managing the dose-response relationships, as exemplified by resveratrol, to avoid paradoxical outcomes.

Reprogramming the Phenotype of TAMs
Monomers derived from traditional Chinese medicine have been shown to regulate TAM polarization and function, thereby modulating anti-tumor immune responses and inhibiting tumor progression. Berberine, a bioactive isoquinoline alkaloid from Coptis chinensis, effectively downregulates M2 macrophage markers, including CD206 and Arg-1, while upregulating major histocompatibility complex class II (MHC-II) and CD40 expression. The decrease of IL-10 production and inhibition of STAT3 phosphorylation in B16F10 melanoma cells treated with recombinant IL-6 (rIL-6) mediate this phenotypic change. Moreover, berberine enhances the secretion of pro-inflammatory cytokines such as IL-1β, IL-12, and TNF-α in response to tumor antigens, thereby promoting CTL activity and expanding the population of IFN-γ-producing CD4⁺ T cells. By disrupting M2 polarization and suppressing the immunosuppressive cytokines IL-10 and TGF-β, berberine effectively restores T cell-mediated anti-tumor cytotoxicity within the tumor microenvironment.42
Ganoderic acid A (GAA), a bioactive triterpenoid compound derived from Ganoderma lucidum, has demonstrated potent anti-tumor effects in both orthotopic and subcutaneous hepatocellular carcinoma (HCC) mouse models. The anti-HCC activity of GAA is mediated, at least in part, by enhancing macrophage-mediated immune responses, including increased phagocytic activity against HCC cells, promotion of M1-type macrophage polarization, and suppression of M2-type polarization. These immunomodulatory effects are associated with the downregulation of colony-stimulating factor 1 receptor (CSF1R) expression in macrophages, as observed in both in vitro experiments and in vivo animal models.117 Astragaloside IV, a bioactive saponin compound derived from Astragalus membranaceus, has been investigated for its anti-tumor properties in a murine model injected with CT26 colon carcinoma cells. This compound significantly inhibited tumor growth by modulating cytokine expression and promoting M1-type reprogramming of TAMs. It downregulates anti-inflammatory cytokines such as TGF-β, IL-10, and VEGF-A, while upregulating pro-inflammatory cytokines such as IFN-γ, IL-12, and TNF, contributing to enhanced anti-tumor immune responses.38
Astragaloside III (AS-III) has been reported to inhibit lung cancer metastasis and angiogenesis, while inducing apoptosis of lung cancer cells in both in vitro and in vivo models. These anti-tumor effects are primarily attributed to the inhibition of M2-type macrophage polarization and the induction of M1 phenotypic transformation, mediated by suppression of the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, AS-III modulates the Akt/mammalian target of rapamycin (Akt/mTOR) pathway, further contributing to its tumor-suppressive activity. These findings highlight the potential of AS-III to reprogram TAMs and reshape the TME, thereby enhancing anti-tumor immunity.36 Dihydroartemisinin (DHA), a derivative of artemisinin, modulates TAM polarization by increasing M1 markers and decreasing M2 markers, enhancing anti-tumor immune responses in murine models.54
Reprogramming TAMs towards an anti-tumor M1 phenotype using TCM monomers (eg., berberine, astragalosides) represents a highly desirable approach to convert foes into allies within the TME. The primary hurdles include ensuring stable and sustained phenotypic switching in the face of strong M2-polarizing signals in the TME, and delivering effective intratumoral concentrations of these agents to exert reprogramming effects.

Activation of the Phagocytic Function of TAMs
Phagocytosis is a critical immune function of TAMs, enabling them to engulf and eliminate tumor cells or debris. This process is tightly regulated and represents a key immunotherapeutic target for anti-tumor immunity. Schisandrin B (Sch B), a lignan compound derived from Schisandra chinensis, has demonstrated tumor-suppressive effects through its modulation of TAM function. Sch B inhibits the phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby suppressing tumor growth and metastasis. While Sch B induces autophagy in hepatocellular carcinoma cells by elevating intracellular reactive oxygen species (ROS) levels, its primary role in activating TAM phagocytosis remains unclear and warrants further investigation.118,119
Baicalin, the principal bioactive flavonoid from Scutellaria baicalensis, promotes M2c macrophage polarization, enhancing phagocytic activity through MERTK receptor upregulation. M2c macrophages exhibit increased expression of genes such as interferon regulatory factor 4 (IRF4), IL-10, and pentraxin 3 (PTX3), while reducing pro-inflammatory cytokines like TNF-α and IL-6. This polarization state distinguishes M2c macrophages from classical M2 macrophages, which exhibit elevated Arg-1 and CD206 expression.40 Ginsenoside Rg3, a bioactive saponin isolated from Panax ginseng, augments macrophage phagocytic capacity through activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) signaling cascades. This activation promotes Fc gamma receptor (FcγR)-mediated phagocytosis, suggesting its potential role in enhancing macrophage-mediated anti-tumor responses.69
In summary, the modulation of TAM function and activation of their phagocytic activity represent promising approaches to enhance anti-tumor immunity. By targeting TAM polarization, recruitment, and function, Chinese herbal monomers offer unique advantages in reshaping the TME. However, further research is needed to optimize dosing, enhance bioavailability, and explore nano-delivery systems to maximize their therapeutic potential in clinical settings.

Targeting MDSCs with Chinese Herbal Medicine Monomers
MDSCs represent a heterogeneous population of immature myeloid cells with potent immunosuppressive functions. These cells primarily originate from bone marrow progenitors and are classified into two main subsets: polymorphonuclear MDSCs (PMN-MDSCs), resembling neutrophils, and monocytic MDSCs (M-MDSCs), sharing features with monocytes. MDSCs play a critical role in tumor-induced immunosuppression, actively regulating immune responses within TME and contributing to immune evasion by suppressing anti-tumor immunity, particularly through inhibition of T cell activation and effector functions.
The expansion and activation of MDSCs are regulated by multiple cytokines and signaling molecules, such as IL-13, IL-14, and IFN-γ. MDSCs release immunosuppressive mediators, including arginase, iNOS, TGF-β, and IL-10, and they facilitate the expansion of Tregs, further contributing to tumor immune escape. Consequently, MDSCs have become a pivotal target in cancer immunotherapy research, with increasing attention on the potential of Chinese herbal monomers to modulate their proliferation, differentiation, and immunosuppressive functions, offering novel therapeutic strategies to enhance anti-tumor immunity.

Inhibition of MDSC Recruitment
Curcumin, a polyphenolic compound from turmeric, has demonstrated effective reduction of MDSC accumulation in both spleen and tumor tissues, promoting their maturation and differentiation within the TME in a Lewis lung carcinoma (LLC) syngeneic mouse model. Furthermore, curcumin inhibits the immunosuppressive activity of MDSCs by downregulating the expression of Arg-1 and reactive oxygen species (ROS) in purified MDSCs isolated from tumor tissues. In tumor-bearing mice, curcumin significantly attenuates MDSC-mediated immune suppression by lowering IL-6 levels in tumor tissues and serum, restricting MDSC expansion and functional activity.120
To enhance curcumin’s therapeutic potential, novel nanoformulations have been developed. Wang et al created a curcumin formulation by conjugating it with the FFE-ss-EE peptide, achieving a high drug-loading efficiency of approximately 40%. This nanostructure, termed nano-curcumin (nano-Cur), exhibits enhanced biological activity, evidenced by downregulation of ARG-1 and iNOS, suppression of ROS generation, and inhibition of IL-10 secretion, contributing to reduced tumor burden by impeding MDSC recruitment and differentiation within the TME.121 Kang et al developed a reactive oxygen species (ROS)- and glutathione (GSH)-responsive drug delivery system, termed CUR/miR155@DssD-Hb nanoparticles (NPs), for the co-delivery of curcumin (CUR) and microRNA-155 (miR-155). This nanoplatform effectively inhibits tumor cell proliferation, enhances dendritic cell (DC) maturation, activates CD8⁺ cytotoxic T lymphocytes, and reduces the presence of immunosuppressive cells, including MDSCs, Tregs, M2-type TAMs, and exhausted T cells, promoting sustained antitumor immune responses and decreasing pulmonary metastasis, offering a promising strategy for melanoma and triple-negative breast cancer (TNBC) treatment.122
Silibinin, a natural flavonoid from Silybum marianum seeds, significantly prolonged the survival of tumor-bearing mice and reduced tumor volume in a 4T1-luciferase murine breast cancer model. It decreases the accumulation of CD11b⁺Gr-1⁺ MDSCs in peripheral blood and tumor tissues and enhances T cell infiltration into the TME, indicating its potential to reverse tumor-induced immunosuppression.123
Inhibiting the recruitment of MDSCs to the TME with agents like curcumin and silibinin is a strategic front-line intervention to prevent the establishment of an immunosuppressive niche. A significant challenge is the systemic nature of MDSC expansion and recruitment, necessitating treatments that maintain effective drug levels over time to continuously block multiple chemokine axes (eg., CXCR2) involved in this process.

MDSC Depletion from Circulation and Tumor Infiltration
Resveratrol (RSV), a polyphenolic compound from Polygonum cuspidatum, significantly reduces both the abundance and immunosuppressive function of MDSCs in a murine model exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD induces a marked reduction of F4/80⁺ macrophages and increases CD11c⁺ dendritic cells, effects reversible by RSV treatment. Mechanistically, TCDD upregulates CXCR2 and ARG-1, promoting MDSC generation and immunosuppressive activity. RSV counteracts these molecular alterations, suggesting its potential as a therapeutic agent to mitigate MDSC-mediated immunosuppression.91 Depleting existing MDSCs from the circulation and tumor, as demonstrated by resveratrol, can provide a rapid reduction in immunosuppressive pressure. The transient nature of this effect poses a challenge, as the bone marrow can continuously replenish MDSCs. Therefore, achieving sustained depletion likely requires prolonged or combination therapy targeting both MDSCs and their upstream production signals.

Targeted MDSC Generation and Differentiation
Chinese herbal medicine monomers inhibit MDSC differentiation from bone marrow precursors and promote their maturation into functional myeloid lineages. Ganoderma lucidum polysaccharide (GLP), derived from Ganoderma lucidum, restores the expression of caspase recruitment domain-containing protein 9 (CARD9), phosphorylated spleen tyrosine kinase (p-Syk), and phosphorylated p65 (p-p65), while increasing indoleamine 2,3-dioxygenase (IDO) levels in MDSCs isolated from Lewis lung carcinoma (LLC) tumor-bearing mice. These molecular changes suggest that GLP regulates MDSC differentiation through the CARD9–NF-κB–IDO signaling axis, contributing to its antitumor effects.64
Ginsenoside Rg3 indirectly modulates immune cells in the bone marrow by inhibiting the biological activity of endothelial progenitor cells (EPCs), attenuating tumor angiogenesis and exerting its immunoregulatory and antitumor effects. Icariin and its derivative icaritin (ICT) promote MDSC differentiation into dendritic cells or macrophages by inhibiting the S100A8/9, STAT3, and AKT signaling pathways, suggesting an effective strategy for reversing MDSC-mediated immunosuppression in the TME.74,124 Xuanhusuo Powder, a traditional Chinese medicinal formula composed of Rhizoma Zedoariae and Rhizoma Corydalis, inhibits MDSC differentiation by downregulating granulocyte colony-stimulating factor (G-CSF), a key cytokine involved in MDSC expansion within the TME, offering anti-breast cancer effects.125
In conclusion, targeting MDSC recruitment, depletion, and differentiation represents a promising approach to enhance anti-tumor immunity. By leveraging Chinese herbal monomers and advanced nano-delivery systems, it is possible to modulate MDSC functions more effectively, offering novel therapeutic strategies in cancer immunotherapy. However, further research is needed to optimize dosing, enhance bioavailability, and explore combination therapies to maximize therapeutic efficiency in clinical settings.

Chinese Medicine Monomer Targeting Tregs
Tregs, a specialized subset of CD4⁺ T cells, play a pivotal role in maintaining immune homeostasis by suppressing excessive T cell activation. Within TME, TAMs, secrete chemokines that recruit Treg precursor cells (TPCs) from the peripheral circulation to the tumor site. These recruited Tregs exert potent immunosuppressive functions, facilitating tumor progression by inhibiting effective antitumor immune responses.126
Li et al demonstrated that Ganoderma lucidum polysaccharides (GLPS) inhibit the Notch1 signaling pathway and downregulate FOXP3 expression by upregulating microRNA-125b (miR-125b). This leads to reduced accumulation and functional activity of Tregs, thereby suppressing liver cancer progression.127
Similarly, artesunate, a flavonoid compound derived from Artemisia annua L., effectively inhibits cyclooxygenase-2 (COX-2) expression in cervical cancer cells, thereby reducing prostaglandin E2 (PGE2) production. This suppression ultimately lowers FOXP3 expression in T cells and decreases the proportion of CD4⁺CD25⁺ T cells in peripheral blood.29
Glycyrrhizic acid, a major bioactive compound in licorice, suppresses phosphorylated signal transducer and activator of transcription 3 (p-STAT3)-mediated immunosuppressive signaling in both Tregs and myeloid-derived suppressor cells (MDSCs) in melanoma. Specifically, it downregulates FOXP3, glucocorticoid-induced TNF receptor (GITR), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) in Tregs, while inhibiting COX-2, PGE2, and Arg-1 in MDSCs.72 Additionally, astragalus polysaccharides (APS) exhibit dual action in immunoregulation, targeting both Treg/Th17 balance and TAMs. In late-stage cancer, APS suppresses hyperactivated Tregs, significantly reduces the IL-10/TGF-β1 ratio, and restores the Treg/Th17 equilibrium. Furthermore, APS inhibits M2 macrophage polarization and promotes M1 phenotype conversion in liver cancer models, thereby contributing to tumor cell proliferation suppression.34
Collectively, these TCM monomers demonstrate the feasibility of targeting Tregs to alleviate their immunosuppressive stranglehold on the TME. However, a central challenge is achieving selective modulation or depletion of tumor-infiltrating Tregs without compromising the vital role of peripheral Tregs in maintaining systemic immune tolerance and preventing autoimmunity. Furthermore, the plasticity and compensatory expansion of Tregs demand strategies that can durably suppress their function.

Application of Traditional Chinese Medicine Monomer and Nano-Delivery System in Tumor Immunotherapy
A nano-drug delivery system represents an advanced drug delivery technology that utilizes various nanocarriers, such as lipids, polymers, inorganic materials, and biomimetic structures, to enable targeted and controlled delivery of therapeutic agents within the body.128–130 While TCM monomers have demonstrated significant potential in tumor immunotherapy, their clinical application is often constrained by pharmacokinetic limitations. These include poor water solubility, resulting in low bioavailability; structural instability, leading to rapid metabolism and degradation; and limited target specificity, increasing the risk of off-target toxicity to normal tissues. The emergence of nano-drug delivery systems presents a promising solution to overcome these challenges by enhancing solubility, improving stability, and enabling precise tumor targeting, thereby optimizing the therapeutic efficacy of TCM-based interventions.131
Nano-delivery systems possess unique physicochemical characteristics, typically in the particle size range of 1–100 nm. Their advantages in drug delivery are multifaceted: a, Enhanced Solubility and Stability: By encapsulating or adsorbing TCM monomers onto nanocarriers, these systems improve the solubility of hydrophobic compounds, protect the drug from environmental degradation, and extend pharmacological activity. b, Controlled Release: Nanodelivery platforms enable sustained release of therapeutic agents in vivo, allowing for precise modulation of drug release rates and site-specific delivery. This ensures effective drug concentrations are maintained within tumor tissues, thereby enhancing therapeutic efficacy. c, Targeting Capabilities: Functionalization of nanocarriers with targeting ligands—such as antibodies, peptides, or aptamers—permits selective recognition of specific receptors or antigens overexpressed on tumor cells. This enables precise delivery of TCM monomers to tumor sites while minimizing off-target effects on healthy tissues (Table 2).

Lipid Nano-Delivery System Combined with Chinese Herbal Monomer
Lipid-based nanoparticles, including liposomes and lipid nanoparticles, feature diverse substructures but commonly comprise at least one lipid bilayer enclosing an aqueous core.77,152 Their favorable biocompatibility, enhanced bioavailability, and tunable physicochemical properties confer significant advantages in drug delivery.156–158 (Table 3).

Rg3-LPs Liposomes
Zhu et al showed that ginsenoside Rg3-loaded liposomes (Rg3-LPs) significantly improve cellular uptake and glioma penetration in vitro and enhance intratumoral delivery in vivo compared to cholesterol-based liposomes. Paclitaxel-loaded Rg3-LPs (Rg3-PTX-LPs) exhibit stronger antiproliferative effects on C6 glioma cells and induce M2-to-M1 macrophage repolarization. In vivo, Rg3-PTX-LPs significantly prolong median survival in glioma-bearing mice by modulating the immune microenvironment, including increasing CD8+ T cells, enhancing the M1/M2 ratio, and reducing Tregs and MDSCs136 (Figure 3Ai–iv). Shuang et al discovered that Rg3-LNPs employ the Rg3 ligand to anchor antigens onto the surface of tumor cells with high Glut1 expression, thereby enhancing recognition by CTLs. Additionally, these nanoparticles accumulate in lymph nodes, where they activate DCs and promote antigen presentation, ultimately priming and expanding CTLs. Furthermore, Rg3-LNPs can synergize with GM-CSF to remodel the tumor immune microenvironment, consequently augmenting the tumor-killing capacity of CTLs.159

Glycyrrhizic Acid (GL)-Lipid Hybrid Nanoplatform (GLLNP)
Xu et al developed a glycyrrhizic acid (GL)-lipid hybrid nanoplatform (TP/GLLNP) loading triptolide (TP) for HCC immunochemotherapy. GL replaced cholesterol as lipid membrane skeleton, endowing nanocarriers with enhanced stability, tumor targeting via GL receptors, and M2-to-M1 macrophage polarization regulation. TP/GLLNP exhibited superior cellular uptake, cytotoxicity, and apoptosis induction in HepG2 cells compared to traditional liposomes. In H22 tumor-bearing mice, it showed enhanced tumor accumulation and synergistic anti-HCC efficacy by combining TP-mediated chemotherapy and GL-mediated immunomodulation, without systemic toxicity. This “three-birds-with-one-stone” strategy provides a novel dual-drug co-delivery system for combined cancer therapy137 (Figure 3B).

PEG-SAB-Lip Nanoparticles
Yunna et al reported that PEG-SAB-Lip suppresses tumor-associated fibroblast activation by downregulating TGF-β1 secretion. This inhibition reduces collagen deposition, enhances intratumoral nanoparticle permeability, reverses the tumor microenvironment through M2-to-M1 macrophage polarization, and limits Treg infiltration. Furthermore, this nanocarrier augments the antitumor efficacy of docetaxel-loaded PEG-liposomes138 (Figure 3C).

CR-Lip Liposomal Platform
Zhang et al developed a multifunctional liposomal delivery platform (CR-Lip) to encapsulate celastrol (CEL) for reprogramming the obesity-associated tumor microenvironment and enhancing cancer immunotherapy. In this system, ginsenoside Rg3 (Rg3) is distributed within the phospholipid bilayer, with glycosyl groups exposed on the liposome surface, potentially facilitating preferential accumulation in tumor tissues via interaction with overexpressed glucose transporter 1. Following accumulation at the tumor site, CR-Lip induces immunogenic cell death (ICD), upregulates PHD3, and inhibits metabolic reprogramming, increasing fatty acid availability. In vivo studies in an obesity-associated melanoma model demonstrated that CR-Lip boosts proinflammatory cytokine secretion, promotes dendritic cell maturation, enhances CD8+ T cell infiltration, and synergizes with aPD-1 therapy to achieve a tumor inhibition rate of 82.1%.134

Silybin Liposomal Formulation
Wu et al designed a liposomal formulation of silybin (SLN/LIP), exhibiting spherical morphology and 75.2 nm particle size, with tumor-specific accumulation and robust immune modulation capabilities. SLN/LIP increased IFN-γ and IL-12 levels, decreased TGF-β, SDF-1, IL-6, and TNF-α, and promoted CTL infiltration, effectively converting “cold” tumors into “hot” ones. Combined with liposomal doxorubicin (DOX/LIP), an inducer of ICD, this system significantly enhances antitumor immunity and overall survival.139

Polymer Nano-Delivery System Combined with Traditional Chinese Medicine Monomer
Polymeric nanoparticles, including nanocapsules and nanospheres, can be further classified into polymers, micelles, and dendrimers. These nanoparticles are synthesized through various techniques such as nanoprecipitation, ionic gelation, and emulsification.160,161 Polymeric nanoparticles are regarded great candidates for drug delivery owing to their biodegradability, water solubility, biocompatibility, biomimicry, non-toxicity, and simplicity of functionalization.162

GLP-APBA-MTX/HCPT Nanoparticles
Zheng et al developed a novel pH-responsive nanoparticle system (GLP-APBA-MTX/HCPT) by conjugating β-glucan-rich Ganoderma lucidum polysaccharides (GLP) with methotrexate (MTX) via 3-aminophenylboronic acid (APBA). The conjugate was coupled with 10-hydroxycamptothecin (HCPT) via nanoprecipitation to create nanoparticles. Compared to free MTX and HCPT, GLP-APBA-MTX/HCPT nanoparticles did not significantly alter IgE levels or leukocyte counts, indicating reduced systemic toxicity. Additionally, the formulation demonstrated potent inhibition of MCF-7 and 4T1 tumor cell viability and achieved a tumor inhibition rate of 73.68%, highlighting its promise as an effective and low-toxicity anti-cancer therapy.163

SK/siIDO1-HMs Micelles
Li et al designed hybrid micelles (SK/siIDO1-HMs) for the co-delivery of shikonin (SK) and small interfering RNA targeting indoleamine 2,3-dioxygenase 1 (siIDO1). To elucidate the antitumor mechanism of SK/siIDO1-HMs, we assessed intratumoral IDO-1 (Figure 4A). Western blot revealed that SK/siIDO1-HMs markedly decreased IDO-1 protein levels compared to SK-HMs (Figure 4B). Concurrently, SK/siIDO1-HMs effectively suppressed IDO-1 activity, as shown by the reduced kynurenine/tryptophan ratio (Figure 4C). Furthermore, this treatment significantly diminished the infiltration of immunosuppressive Tregs (Figure 4D). These results indicate that SK/siIDO1-HMs confer synergistic antitumor efficacy by inducing ICD and mitigating IDO1-mediated immunosuppression. These micelles exhibited prolonged systemic circulation, enhanced tumor accumulation, and rapid cytoplasmic release, thereby triggering immune responses through remodeling of the tumor immune microenvironment.164

Nano-Delivery System of Chinese Medicine Monomer Combined with Inorganic Material
Inorganic nanoparticles, such as gold, iron, and silica, exhibit unique magnetic, radioactive, and photothermal properties.165,166 These physicochemical characteristics make them highly valuable for applications in cancer detection, imaging, and photothermal therapy in both preclinical and clinical settings. A major advantage of gold nanoparticles lies in their facile surface modification and strong binding affinity, enabling non-covalent loading of TCM monomers while preserving stability and biocompatibility.167

EGCG-Png Gold Nanoparticles
Gold nanoparticle-conjugated EGCG (EGCG-png) demonstrates superior therapeutic efficacy compared to free EGCG in bladder cancer treatment. EGCG-png exerts antitumor effects by inducing apoptosis and enhancing immune responses, while also mitigating EGCG-associated hepatotoxicity at high doses.168

GLP-Au Gold Nanocomposite
Hang et al developed a Ganoderma lucidum polysaccharide-coated gold nanocomposite (GLP-Au) that effectively promotes DC activation (Figure 5A–D). Combining GLP-Au-stimulated DCs with T cells leads to increased T cell proliferation and a higher fraction of CD4⁺/CD44⁺ memory T cells when paired with doxorubicin (Figure 5E–L).148

Magnetic Nanoparticles (MNPs)
Magnetic nanoparticles have gained prominence due to their small size, excellent colloidal stability, favorable biocompatibility, tumor-targeting capacity, and efficient heat generation under magnetic fields.169 Chiang et al proposed a magnetically guided therapeutic platform combining a fucosan-dextran-based nanocarrier (IO@FuDex 3) with checkpoint blockade (anti-PD-L1) and T cell co-stimulation (anti-CD3 and anti-CD28). This strategy reactivates tumor-infiltrating lymphocytes and targets tumors via magnetic guidance, reducing off-target effects. Notably, treatment with IO@FuDex 3 extended median survival from 32 to 63 days, significantly outperforming soluble anti-PD-L1 at subtherapeutic doses (<1%).170

Nano-Delivery System of Traditional Chinese Medicine Monomer Combined with Bionic Material
Biomimetic nano-delivery systems are nanocarriers designed to mimic the structure and biological functions of endogenous substances, offering excellent biocompatibility, precise targeting, and controlled drug release. Representative biomimetic materials include cell membrane-derived vesicles, such as those sourced from red blood cells or tumor cells. These materials facilitate immune evasion, extend systemic circulation time, and enable tumor-specific delivery via homologous membrane targeting.171,172

Exosome-Based Delivery
Exosomes are nanoscale extracellular vesicles originating from endosomal compartments, characterized by small size and complex biochemical composition and structure.173 Cui et al employed tanshinone IIA (TanIIA) and glycyrrhizic acid (GL), both traditional Chinese medicine-derived STAT3 inhibitors, to formulate self-assembled TanIIA-GL nanomicelles (TGM). These nanomicelles were encapsulated using endogenous serum-derived exosomes, and CpG oligonucleotides -agonists of Toll-like receptor 9 were functionalized onto the exosome surface, forming immune exosomes loaded with TCM-based nanomicelles (CpG-exo/TGM). The resulting CpG-exo/TGM demonstrated the ability to evade mononuclear phagocyte system (MPS) clearance, penetrate the blood-brain barrier via transferrin receptor-mediated endocytosis, and enable efficient intratumoral drug release. Co-administration of CpG-exo/TGM with temozolomide significantly enhanced antitumor efficacy and reduced the risk of postoperative recurrence.144

Exosome-Like Nanoparticles Derived from Dipsacus Asper (DAELNs)
Lu et al investigated the effects of exosome-like nanoparticles derived from Dipsacus asper (DAELNs) on osteosarcoma in both in vitro and in vivo models. In vitro, DAELNs suppressed proliferation, migration, and invasion of osteosarcoma cells, while promoting apoptosis. In xenograft nude mouse models, DAELNs markedly inhibited tumor growth. Mechanistically, DAELNs induced apoptosis via activation of the P38/JNK signaling cascade. Biodistribution studies with DiD-labeled DAELNs confirmed tumor-specific accumulation and demonstrated minimal hepatotoxicity and nephrotoxicity upon histological examination.174

Cell Membrane Vesicles
Cell membrane vesicles are nanoscale structures derived from various membrane sources, including single-cell types (eg, stem cells, immune cells, blood cells, and bacterial membranes), hybrid membranes, or membranes fused with liposomes. These vesicles exhibit intrinsic biocompatibility, targeting ability, and therapeutic potential. They can transport therapeutic agents such as drugs, genes, or signaling molecules that interact with target cell receptors, enabling immune evasion and precise drug delivery.175

GACS-Cur@RBCm Nanoparticles
Guo et al synthesized glycyrrhizic acid (GA)-aps-disulfide bond (DTA)-curcumin nanoparticles (GACS-Cur) using a dialysis-based self-assembly method. To prolong systemic circulation and enhance immune evasion, GACS-Cur was encapsulated in erythrocyte membranes (GACS-Cur@RBCm). Upon encountering the glutathione-rich tumor microenvironment (TME), GACS-Cur disassembles, releasing its cytotoxic payload into HCC cells. Additionally, this encourages the invasion of CD8+ T cells and triggers the release of TNF-α, IFN-γ, and IL-2. The formulation demonstrates precise tumor targeting and robust antitumor activity in liver cancer models.145

GDNPs Exosomal Nanoparticles
Cao et al isolated ginseng-derived extracellular vesicle-like nanoparticles (GDNPs) from ginseng roots and used them as immunostimulants to reprogram M2 macrophages, implicating anti-melanoma activity via TLR4 and MyD88 signaling pathways. This reprogramming led to enrichment of M1 macrophages and T cells within the tumor, enhancing antitumor immunity and confirming GDNPs’ macrophage-dependent mechanism in melanoma suppression.146

Mannose-Modified Red Blood Cell Membranes Nanoparticles
Han et al developed PLGA nanoparticles co-loaded with PLB, DIH, and NH4HCO3, a pH-sensitive adjuvant. To produce a targeted nanoformulation, these nanoparticles were further functionalized using red blood cell membranes modified with mannose. As shown in the study (n=6), the combination nanoformulation (Comb-NP) effectively suppressed HCC progression over a 20-day period, extending median survival from 28 days (PBS group) to over 90 days (Figure 6A–C). Analysis of tumors on day 18 revealed an increase in immunostimulatory cells and a decrease in immunosuppressive cells, demonstrating the strategy’s efficacy in reversing the immunosuppressive tumor milieu (Figure 6D–G). This design markedly improved pharmacokinetic behavior and tumor selectivity of traditional Chinese medicine payloads. It modulates the “cold” tumor microenvironment by inducing ICD and triggering systemic immune responses. Consequently, this chemoimmunotherapy strategy reverses the immunosuppressive tumor milieu.176

Traditional Chinese Medicine Monomer Combined with Other Nano-Delivery Systems

Mesoporous Microfibers (SMF) Vaccine Scaffolds
Astragaloside IV (AS-IV) can be formulated into mesoporous microfibers (SMF) without excipients. These injectable SMFs self-aggregate in vivo to form macroporous three-dimensional scaffolds. Such scaffolds recruit DCs into the inter-fiber pores and facilitate their maturation through NLRP3 pathway activation. AS-IV-based scaffold vaccines, lacking toxic or costly adjuvants, show strong immunostimulatory activity in melanoma and breast cancer models, eliciting potent antitumor immune responses. These scaffolds further enhance therapeutic efficacy when combined with approved TLR-4 agonists and immune checkpoint inhibitors.177

NRA Quantum Dots
Realgar, a traditional mineral medicine, possesses notable anticancer properties and is a promising adjuvant in oncology. Its clinical translation is limited by poor solubility and low bioavailability. Wang et al developed realgar quantum dots (NRA QDs) conjugated with 6-AN and encapsulated them in a hyaluronic acid-modified, pH-sensitive dextran hydrogel (DEX-HA gel) for improved delivery. The resulting NRA@DH gel exerts chemotherapeutic effects and acts as a sustained ROS generator. It inhibits the pentose phosphate pathway (PPP), reducing NADPH levels by blocking GSSG-to-GSH conversion. As a result, intracellular GSH is depleted, promoting ROS accumulation and enhancing radiotherapy efficacy. In tumor-bearing mice, NRA@DH gel inhibited proliferation, migration, and tumor growth, improved motor coordination, and extended survival via combined chemo-radiotherapy.178

LNT-UA Nanopharmaceutical
Mao et al formulated LNT-UA, a carrier-free nanopharmaceutical derived from ursolic acid (UA) and lentinan (LNT), using a simple nanoprecipitation method for colorectal cancer immunotherapy. In CT26 CRC models, LNT-UA modulated the immunosuppressive TME and activated both innate and adaptive immunity to suppress tumor progression. LNT-UA significantly inhibited primary and metastatic tumor growth, doubling median survival in bilateral tumor models. In a spontaneous colorectal cancer model, sequential administration of LNT-UA and αCD47 markedly reduced tumor burden and nodule size.150

Comparative Analysis of Nano-Delivery Platforms
The preceding sections have detailed a variety of nano-delivery systems designed to enhance the therapeutic efficacy of TCM monomers. A critical comparative analysis of their fundamental characteristics, strengths, and weaknesses is essential to guide rational platform selection for future research and clinical translation.
Lipid Nano-delivery System are among the most clinically advanced nanocarriers. Their primary advantages include excellent biocompatibility, proven ability to encapsulate both hydrophilic and hydrophobic drugs, and a well-established, scalable manufacturing process (eg., extrusion, microfluidics). Functionalization with PEG (stealth coating) or targeting ligands further enhances their circulation time and tumor accumulation.179 However, their limitations include potential drug leakage during storage, batch-to-batch variability, and sometimes insufficient drug loading capacity for certain TCM compounds.180 Lipid Nano-delivery System benefits from decades of research, with multiple FDA-approved products (eg., Doxil®, Onpattro®). Their safety profiles are relatively well-understood, and Good Manufacturing Practice (GMP) production is feasible. The successful integration of TCM monomers like ginsenoside Rg3 and glycyrrhizic acid as both membrane components and active agents (eg., Rg3-PTX-LPs, TP/GLLNP) demonstrates a highly innovative and translatable strategy that leverages the intrinsic properties of TCM compounds.
Polymer Nano-delivery System offer high design flexibility. Their key advantages are controllable biodegradation rates, sustained drug release profiles, and the capacity for precise surface engineering.181 Systems like SK/siIDO1-HMs demonstrate the potential for co-delivering small molecules and nucleic acids. The main challenges involve the potential toxicity of polymer degradation products, complex synthesis/purification steps that can affect reproducibility, and relatively lower drug loading efficiency compared to some lipid systems.182,183
Inorganic Nano-delivery System (eg., gold, silica, magnetic NPs) possess unique physicochemical properties. Their strengths lie in their exceptional stability, ease of surface modification, and multifunctionality (eg., imaging contrast, photothermal therapy). GLP-Au nanocomposites, for instance, combined immunotherapy with potential diagnostic capabilities. Three types of rod-like gold-mesoporous silica nanoparticles (termed bare AuNPs, core-shell Au@mSiO2NPs, and Janus Au@mSiO2NPs) were specially designed, and the effects of these AuNPs on cellular uptake, toxic behavior, and mechanism were then systematically studied. The results showed that bare AuNPs were more toxic to human breast cancer cells. The significant drawbacks that hinder clinical translation are concerns regarding long-term toxicity and biodistribution (potential for organ accumulation), uncertain biodegradation pathways, and generally more complex and costly synthesis.184,185
Biomimetic Nano-delivery System (eg., exosome, cell membrane-coated NPs) represent a cutting-edge strategy. Their greatest advantage is superior biocompatibility and innate ability to evade immune clearance, leading to prolonged circulation and enhanced targeting. Platforms like CpG-exo/TGM and mannose-modified RBC membrane NPs show impressive blood-brain barrier penetration and tumor-specific accumulation. The primary limitations are the technical challenges in scalable production with consistent quality, difficulties in achieving high and standardized drug loading, and the complexity of fully characterizing these biologically derived components.186,187

Discussion
In recent years, immunotherapy has changed the landscape of cancer treatment with its significant improvement in patient outcomes. However, its efficacy remains limited to a subset of patients, largely due to intrinsic resistance mechanisms and the immunosuppressive characteristics of TME.188,189 While ICIs and CAR-T cell therapy have demonstrated success, challenges such as low immune infiltration (“cold” tumors), T cell exhaustion, and immune-related adverse events continue to constrain their broader application.190 The TME plays a central role in shaping therapeutic outcomes and regulating tumor immune escape and therapy resistance.191,192 Immunosuppressive populations such as TAMs, MDSCs, and Tregs contribute to T cell dysfunction through cytokine secretion, immune checkpoint upregulation, and ECM remodeling.99,193–195 Consequently, effective strategies that modulate the TME are critical for enhancing immunotherapy responsiveness.
TCM monomers have shown potential in remodeling the immune landscape of the TME. Compounds like curcumin, ginsenosides, berberine, and triptolide exert multi-target immunomodulatory effects, such as reprogramming TAMs, reducing MDSC accumulation, and restoring T cell function.196,197 However, their clinical application is hampered by poor solubility, low bioavailability, and inadequate tumor targeting, which limit effective concentrations within the tumor site. In this context, nanotechnology offers promising solutions to these delivery challenges. By improving pharmacokinetics, stability, and tumor accumulation, nano-delivery systems enhance the therapeutic efficacy of TCM monomers. For instance, pH-sensitive nanocarriers can facilitate site-specific release in the acidic TME, while ligand-modified systems enable active targeting of immune cells or tumor sites.198–200 Additionally, co-delivery strategies integrating TCM compounds with ICIs or chemotherapeutics have demonstrated synergistic effects by modulating the TME and promoting immunogenic cell death.201–203
Nevertheless, the clinical translation of TCM-based nanomedicine still faces several challenges. First, the heterogeneity of TCM monomers, including variability in purity, source, and preparation, may affect formulation reproducibility and pharmacodynamics. Second, the safety and long-term toxicity of certain nanomaterials require comprehensive evaluation, especially regarding immune compatibility. Third, large-scale production, cost-effectiveness, and regulatory approval remain major hurdles that must be addressed before widespread clinical application. The future research should focus on the rational design of multifunctional nanoplatforms tailored for specific TCM compounds and tumor types. Integration of advanced technologies such as artificial intelligence, bioinformatics, and single-cell sequencing may guide the personalized selection of TCM agents and predict therapeutic responses. Moreover, combination regimens incorporating TCM-nanoformulations with ICIs, cancer vaccines, or adoptive cell therapies could offer synergistic benefits and expand the responder population in immunotherapy.
Looking forward, the next frontier in TCM-based nanomedicine lies in the rational design of more intelligent and adaptive delivery systems. Emerging nanotechnological strategies offer compelling solutions to current challenges. First, the development of “cascade-responsive” or logic-gated nanocarriers is promising. These systems can be engineered to sequentially respond to multiple, specific TME stimuli (eg., overexpressed enzymes followed by acidic pH), ensuring highly precise spatiotemporal drug release only at the intended site, thereby maximizing therapeutic efficacy and minimizing systemic toxicity.204 Second, biomimetic technologies are advancing beyond simple cell membrane coating. By leveraging synthetic biology tools, future nanosystems can be endowed with dynamic, bioinspired functions—such as surfaces that mimic the recruitment signals of specific immune cells—to achieve active, context-dependent homing to immunosuppressive niches within the TME.205,206 Furthermore, the convergence of nanomedicine with real-time sensing could pave the way for closed-loop therapeutic systems. These “smart” platforms would not only deliver TCM monomers but also monitor local biomarkers (eg., cytokine levels) and adaptively adjust their payload release to maintain an optimal immunomodulatory state, representing a paradigm shift towards personalized and adaptive cancer immunotherapy.207 The integration of these sophisticated strategies with the multi-targeting philosophy of TCM holds transformative potential for robustly and intelligently reprogramming the immunosuppressive TME.
To bridge the promising preclinical findings discussed herein to tangible clinical benefits, a focused effort on translational science is imperative. The key steps for this transition must be systematically addressed. First, the scalable and reproducible production of TCM-based nano-formulations under Good Manufacturing Practice (GMP) standards is a fundamental prerequisite to ensure consistent quality, stability, and safety for human use. Second, beyond proof-of-concept models, rigorous validation in immunocompetent, patient-derived xenograft (PDX) models or humanized mouse models that better recapitulate the human immune system and tumor heterogeneity is crucial for predicting clinical efficacy. Third, comprehensive pharmacokinetic and pharmacodynamic (PK/PD) studies, including detailed assessments of biodistribution, organ-specific accumulation, and clearance pathways, are essential to understand the in vivo fate of these nanosystems. Finally, thorough toxicological evaluation—extending beyond acute toxicity to include chronic toxicity, immunotoxicity, and potential off-target effects—must be conducted in relevant animal species to establish a safety profile that supports Investigational New Drug (IND) application. Addressing these translational pillars with the same rigor applied to mechanistic discovery will be critical for advancing TCM-based nanomedicine from the bench to the bedside.
In conclusion, the immunosuppressive TME remains a formidable barrier to effective cancer immunotherapy. TCM monomers represent a valuable reservoir of bioactive compounds capable of reprogramming the immune landscape, yet their clinical utility is constrained by delivery limitations. Nanotechnology-based delivery systems offer a powerful platform to overcome these barriers, enabling precise, controlled, and targeted modulation of the TME. Continued interdisciplinary research integrating traditional medicine, nanoscience, and immuno-oncology will be critical to translating these innovations into clinical reality.

Conclusion
This review systematically elucidates the critical roles of immunosuppressive cell populations TAMs, MDSCs, and Tregs in fostering a tumor-promoting microenvironment and contributing to immunotherapy resistance. We have comprehensively summarized the compelling evidence that numerous TCM monomers, such as curcumin, berberine, ginsenoside Rg3, and glycyrrhizic acid, can directly target these cells to reverse immunosuppression, offering a unique multi-target and low-toxicity approach to “heat up” cold tumors.
However, the inherent pharmacokinetic drawbacks of these compounds—including poor solubility, instability, and non-specific biodistribution—severely limit their clinical translation and therapeutic efficacy. The integration of advanced nano-delivery systems (eg., liposomes, polymeric nanoparticles, inorganic carriers, and biomimetic vesicles) emerges as a transformative strategy. These systems not only overcome the delivery barriers but also enhance the immunomodulatory potency of TCM monomers through improved tumor targeting, controlled release, and intelligent responsiveness to the TME. The reviewed nano-formulations demonstrate synergistic potential in reprogramming the immune landscape, promoting immunogenic cell death, and enhancing the efficacy of conventional therapies.
Looking forward, the convergence of TCM and nanotechnology represents a promising frontier in cancer immunotherapy. To advance this field, future efforts must prioritize: (1) the rational design of multifunctional and tumor-microenvironment-responsive nanoplatforms tailored to specific TCM agents; (2) rigorous investigation into the long-term safety, biocompatibility, and potential immunotoxicity of these complex nano-formulations; and (3) the exploration of personalized combination regimens that integrate TCM-based nanomedicines with immune checkpoint inhibitors, adoptive cell therapies, or conventional modalities. By fostering deeper interdisciplinary collaboration among pharmacologists, material scientists, and clinical oncologists, the translation of these sophisticated TCM-nano strategies from bench to bedside can be accelerated, ultimately providing new hope for overcoming tumor immunosuppression and improving patient outcomes.