Research progress on the impact of curcumin on immune responses in breast cancer

1 Introduction

Breast cancer (BC) is the most prevalent malignant tumor among women worldwide. In 2022, the global incidence and mortality of BC in women were approximately 2.309 million and 666,000 cases, ranking second and fourth, respectively, among all malignancies [1]. It is projected that by 2040, the incidence and mortality rates of BC will increase by 40 and 50%, respectively, due to population growth and aging [2]. Clinically, BC presents several subtypes, including hormone receptor-positive, human epidermal growth factor receptor 2 (HER2) overexpression, and triple-negative subtypes [3]. These subtypes exhibit distinct biological behaviors and treatment sensitivities, thereby necessitating personalized therapeutic approaches. In addition, BC presents heterogeneity in clinical features, including tumor size, lymph node involvement, and histological grading. This complexity and diversity underscore the need for a comprehensive approach in BC clinical management, considering multiple factors to develop optimal treatment strategies. Traditional treatment modalities for BC include surgical resection, radiotherapy, chemotherapy, and endocrine therapy. Although these approaches have achieved some success, limitations persist, including poor prognosis, adverse effects, and drug resistance [4].

In the search for new therapeutic strategies, scientists have increasingly turned their attention to natural products, particularly those compounds with anti-inflammatory, antioxidant, anti-proliferative, and immune-modulatory properties [5]. As part of complementary and alternative medicine, plant-based therapies have been extensively researched and applied over the past few decades. These therapies are often grounded in centuries-old traditional medical knowledge, with several of them being validated by modern science as effective adjuncts in cancer treatment. For instance, curcumin, a polyphenolic compound extracted from the rhizome of turmeric, has garnered significant attention due to its distinctive biological activities.

The history of curcumin dates back thousands of years in traditional Asian medicine, such as Ayurveda and Traditional Chinese Medicine, where it was used as a spice, dye, and treatment for various health conditions [6]. In recent years, an increasing body of research has shown that curcumin not only possesses potent anti-inflammatory and antioxidant properties but also exhibits significant anti-tumor effects against various types of cancer [7]. Its mechanisms of action are multifaceted, involving the inhibition of cancer cell proliferation, induction of apoptosis, alteration of the cell cycle, modulation of tumor-associated signaling pathways, and enhancement of the immune system to combat cancer. Studies demonstrated that curcumin can promote apoptosis in BC cells and influence their cell cycle progression [8]. Furthermore, research indicates that curcumin effectively reduces the viability of human pancreatic cancer cell lines, with IC₅₀ values ranging from 8.67 to 20.35 µmol/L, showing strong anti-proliferative activity [9].

However, the immune response in BC is a complex process that involves the participation of various immune cells, including T cells, B cells, macrophages, and natural killer (NK) cells. An ideal immune response should eliminate cancer cells, suppress tumor growth and metastasis, and thereby control or cure the disease. Unfortunately, tumors can evade immune surveillance through mechanisms such as altering antigen expression, inhibiting immune cell activity, or inducing immune tolerance, which limits the effectiveness of the immune response. Therefore, the research and development of novel therapeutic strategies that can enhance the immune response are crucial for improving the efficacy of BC treatment.

Given the unique properties of curcumin and its impact on the immune response in BC, this review focused on how curcumin modulated the immune system to combat BC, evaluating its potential as a therapeutic option. This work discussed in detail the pharmacological effects of curcumin, its specific impact on the BC immune response, and the latest research developments in this area. It was hoped that this review would not only provide valuable insights into curcumin and its application in BC treatment but also inspire further exploration of plant-based therapies and natural products in cancer treatment.

2 Characteristics of curcumin

Curcumin is primarily extracted from the rhizomes of Zingiberaceae plants such as turmeric (Curcuma longa L.) and zedoary (Curcuma zedoaria (Berg.) Rosc.), and additionally, the rhizomes of plants from the Araceae family, such as calamus (Acorus calamus L.), serve as another important source of curcumin [10]. Its chemical formula is C₂₁H₂₀O₆ (Figure 1). Its earliest recorded medicinal use dates to the 6th century BCE in ancient Indian medical texts. For a long period thereafter, curcumin was primarily used as a food additive. It was not until 1910 that researchers deduced the accurate chemical structure of curcumin, leading to subsequent systematic investigations into its chemical properties and pharmacological effects [11]. Curcumin is a polyphenolic compound characterized by two benzene rings and an elongated side chain in its chemical structure. It possesses potent antioxidant and anti-inflammatory properties, mitigating oxidative damage and inflammatory responses by interacting with free radicals. Research has indicated that curcumin exhibits antioxidative, anti-inflammatory, anti-tumor, anti-platelet aggregation, antibacterial, antiviral, and cholesterol-lowering effects. Additionally, some studies have suggested its neuroprotective and cardioprotective properties. Curcumin also holds potential benefits in the prevention and treatment of diseases such as cancer, cardiovascular disorders, diabetes, and arthritis [12].

Figure 1

Structural diagram of curcumin.

In 1985, pioneering research first proposed the anticancer properties of curcumin, highlighting its potential in counteracting inflammation and preventing cancer by scavenging free radicals or activating endogenous mechanisms to counteract oxidative stress triggered by carcinogenic agents. Subsequent studies indicated that curcumin not only exerts a direct inhibitory effect on tumor cell growth but also modulates multiple signaling pathways and molecular targets, thereby inhibiting processes such as tumor metastasis, invasion, and angiogenesis [13]. These findings have propelled further exploration and investigation of curcumin as a potential anticancer agent.

Although curcumin is renowned for its potent antioxidant and anti-inflammatory properties, which alleviate oxidative damage and inflammatory responses through interaction with free radicals, its application in BC treatment faces several key challenges. First, curcumin has low bioavailability, primarily due to its poor water solubility and rapid metabolism. This low bioavailability limits curcumin’s ability to reach effective concentrations in vivo, thereby affecting its clinical efficacy. Second, studies noted that curcumin can induce apoptosis in cancer cells and alter the cell cycle; however, this effect may vary across different BC subtypes, particularly in tumors with strong drug resistance [14].

Curcumin, a natural compound with potential anticancer activity, faces limitations in its application due to its low bioavailability. To overcome this challenge, scientists have explored various delivery strategies, particularly the use of nanotechnology and liposomal technology. Polymer-based nanoparticles have attracted attention due to their good biocompatibility and adjustable release characteristics. For instance, poly(lactic-co-glycolic acid) (PLGA) nanoparticles have been extensively studied to improve drug stability and prolong its therapeutic duration. In contrast, lipid-based nanoparticles, such as solid lipid nanoparticles and nanostructured lipid carriers, are renowned for their high drug-loading capacity and better physical stability. Inorganic nanoparticles, such as silica or gold nanoparticles, although posing challenges in terms of biodegradability, offer unique optical and electrical properties, making them suitable for imaging-guided therapy. By comparing the advantages and disadvantages of these different nanoparticle systems, a basis can be established for selecting the most suitable carrier for curcumin delivery.

Additionally, liposomes, as another important form of drug delivery system, are directly influenced by the selection of their components, which affects encapsulation efficiency, stability, and drug release behavior. Common components, such as phosphatidylcholine (PC) and cholesterol, are used to construct stable liposomal structures. Increasing the proportion of cholesterol can enhance the stability of liposomes and reduce drug leakage. Furthermore, surface modification techniques, such as PEGylation, can improve the circulation time and targeting ability of liposomes. By thoroughly evaluating the combinations of different liposomal components and their stability characteristics, the delivery efficacy of curcumin can be optimized.

In addition to traditional nanoparticles and liposomes, novel delivery systems such as dendrimers and hydrogels have shown great potential. Dendrimers, with their highly branched three-dimensional structure, are capable of efficiently encapsulating and protecting curcumin while providing high cellular uptake efficiency. Hydrogels, owing to their excellent biocompatibility and easily tunable physicochemical properties, demonstrate advantages in local drug delivery. These novel delivery systems not only enhance the solubility and stability of curcumin but also improve its targeting specificity and reduce side effects.

The efficacy of each delivery system needs to be further validated through detailed pharmacokinetic studies. Data on the absorption, distribution, metabolism, and excretion (ADME) processes of the drug in vivo can help us better understand how different formulations affect the bioavailability of curcumin. For example, nanoparticles may extend the drug’s half-life by altering its tissue distribution pattern, while liposomes could improve bioavailability by reducing the hepatic first-pass effect.

Finally, although laboratory studies demonstrated the potential of these delivery systems in enhancing curcumin’s bioavailability, many challenges remain in the clinical translation process. Current research is largely limited to animal experiments, and further clinical trials are needed to verify their safety and efficacy. Additionally, cost-effectiveness analysis is an important consideration, especially in large-scale production.

The dose-dependent toxicity of curcumin has been explored in several preclinical and clinical studies. In animal models, high doses of curcumin may lead to side effects such as gastrointestinal discomfort, elevated liver enzyme levels, and immune system suppression [15]. However, in human studies, curcumin generally demonstrates good tolerance, with no severe toxic reactions observed even at higher doses [16]. Nonetheless, further research is needed to determine the optimal dosage range in different populations and to clarify its dose-response relationship.

When used in combination with various chemotherapeutic agents, curcumin may produce either synergistic or antagonistic effects. For instance, studies have shown that curcumin can enhance the anticancer effects of cisplatin while reducing its nephrotoxicity. On the other hand, curcumin may also affect the metabolic pathways of certain drugs, particularly by inhibiting the cytochrome P450 enzyme system, which can increase the plasma concentrations and potential toxicity of other drugs. Therefore, careful consideration of the interactions between curcumin and other chemotherapeutic agents is essential when designing combination therapies to avoid unnecessary side effects and optimize therapeutic outcomes.

The long-term safety of curcumin is another important consideration. Although short-term use of curcumin is generally considered safe, data on its long-term safety are relatively limited. Overall, the incidence of adverse events associated with curcumin is low, but further large-scale clinical trials are needed to validate its safety. Safety data for pregnant women, lactating women, and children are particularly limited. Given that curcumin may impact fetal development or breastfeeding, it should be used with caution in these populations. There may be individual variations in response to curcumin, potentially linked to genetic factors. Future research should focus on the impact of genetic polymorphisms on curcumin metabolism and efficacy to inform personalized treatment strategies. As a natural product, curcumin is often used in combination with other herbs or supplements. Understanding how these combinations affect curcumin’s bioavailability and safety is crucial. In conclusion, while existing evidence suggests that curcumin has good safety, a comprehensive safety assessment is still needed before its widespread use in BC treatment.

3 Impact of curcumin on the immune response in BC

Given the inherent challenges posed by tumor immune evasion mechanisms, immune cell functional states, and immune suppression within the tumor microenvironment (TME), curcumin’s multifaceted effects – such as its antioxidant, anti-inflammatory, anti-tumor, anti-platelet aggregation, antimicrobial, antiviral, and cholesterol-lowering properties – regulate the immune response by promoting anti-tumor T-cell activity and altering the cytokine milieu. These effects may address issues observed in BC immune responses, potentially leading to improvements in BC immunotherapy.

Curcumin has been shown to alter macrophage polarization, converting them from the pro-tumor M2 phenotype to the anti-tumor M1 phenotype [17]. This transition helps create a microenvironment conducive to immune-mediated tumor cell clearance. Additionally, curcumin can enhance the activity of NK cells, increasing their ability to recognize and kill tumor cells. Curcumin interferes with key signaling pathways, such as the phosphoinositide 3-kinase (PI3K)/AKT serine (AKT)/threonine kinase/mammalian target of rapamycin pathway, which are closely associated with tumor cell survival. By inhibiting these pathways, curcumin not only reduces cancer cell proliferation but also promotes apoptosis [18]. Moreover, curcumin upregulates p53 gene expression, further enhancing its anti-cancer effects. In recent years, immune checkpoint inhibitors have become one of the effective strategies for treating certain types of cancer. Curcumin has shown synergistic effects with these drugs, such as enhancing T-cell-mediated anti-tumor immune responses by reducing PD-L1 expression levels.

The combined mechanism of action of curcumin and immune checkpoint inhibitors involves multiple levels. First, curcumin can inhibit the inflammatory response by modulating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and reduce the expression of PD-L1, thereby relieving the immune suppression within the TME. Second, curcumin can activate the Nrf2 pathway, enhancing the antioxidant defense system and protecting immune cells from oxidative stress-induced damage, thus maintaining their functional integrity. Furthermore, curcumin promotes the maturation and antigen-presenting capacity of dendritic cells, further enhancing T-cell-mediated anti-tumor immune responses. This multi-target, multi-level mechanism of action makes curcumin an ideal candidate for combination therapy with immune checkpoint inhibitors.

Currently, clinical trials on the combination of curcumin and immune checkpoint inhibitors are still in the early stages. Although some preliminary studies suggest that this combination holds potential, most research is focused on preclinical models or small-scale Phase I/II clinical trials. The combination of curcumin and immune checkpoint inhibitors may yield significant anti-tumor effects. In terms of safety, while curcumin is generally considered safe, high doses may cause mild-to-moderate gastrointestinal discomfort and other side effects. Therefore, optimizing the dosage and administration regimen of curcumin is crucial for ensuring the safety of combination therapy.

Determining the optimal sequencing strategy is essential for maximizing the efficacy of the combination therapy of curcumin and immune checkpoint inhibitors. Studies have shown that different dosing sequences may affect treatment outcomes. For example, administering curcumin first to prepare the TME, followed by immune checkpoint inhibitors, may be more effective than simultaneous administration. Additionally, developing personalized treatment plans based on the patient’s specific condition and biomarker characteristics is one of the key strategies to enhance therapeutic efficacy.

The development of reliable biomarkers is crucial for guiding the selection of combination therapy with curcumin and immune checkpoint inhibitors. Existing studies have shown that biomarkers such as PD-L1 expression levels, tumor mutation burden, and microsatellite instability can predict the efficacy of immune checkpoint inhibitors. Future research should focus on identifying new biomarkers, particularly those that can reflect the mechanisms of action of curcumin, such as NF-κB activity and Nrf2 expression levels. These biomarkers can not only help identify patients who are most likely to benefit from combination therapy but also provide a basis for personalized treatment. Figure 2 illustrates the various pathways involved in immune responses.

Figure 2

Different pathways of immune response.

4 Effects of curcumin on immune cell function

Curcumin has the capacity to modulate the activity and functionality of immune cells, including macrophages, T cells, B cells, and NK cells. In BC patients, curcumin can regulate the activity and function of tumor-infiltrating lymphocytes, thereby enhancing anti-tumor immune responses. Monocytes and macrophages constitute pivotal cells within the innate immune system, engaging in defense against invading pathogens, phagocytosis of dead cells, presentation of antigens via major histocompatibility complex class I and II molecules, and production of various pro-inflammatory cytokines and chemokines (such as interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α). Upon sensing inflammatory cues, macrophages initially adopt an M1 phenotype, releasing pro-inflammatory cytokines in response. When the M1 phenotype fails to counteract stimuli and becomes extensively accumulated, it can lead to tissue damage. At this point, M2 macrophages, in contrast, secrete abundant anti-inflammatory factors, inhibiting inflammation and restoring tissue homeostasis. Tumor-associated macrophages (TAMs) polarize towards an M2 phenotype within the TME, characterized by elevated expression and release of IL-10 and transforming growth factor (TGF)-β, along with reduced IL-12. Signal transducer and activator of transcription 3 (STAT3) is a key intracellular signaling molecule involved in regulating various physiological processes, including cell proliferation, survival, apoptosis, and immune responses. In cancer, particularly in the TME, aberrant activation of STAT3 is widely recognized as being associated with the promotion of tumor progression. Under normal conditions, macrophages can be classified into two main phenotypes: M1 (classically activated) and M2 (alternatively activated). M1 macrophages promote anti-tumor immune responses by secreting pro-inflammatory cytokines, while M2 macrophages support tissue repair and suppress inflammation by secreting anti-inflammatory cytokines. However, in the TME, persistent activation of STAT3 leads to the polarization of macrophages toward the M2 phenotype, thereby promoting tumor growth and metastasis. STAT3 activation also helps tumor cells evade host immune surveillance by upregulating the expression of immune checkpoint molecules, such as PD-L1. Additionally, STAT3 is involved in regulating tumor-associated angiogenesis and epithelial–mesenchymal transition, both of which are key steps in tumor metastasis. Curcumin, as a natural compound, has been shown to effectively inhibit STAT3 activity, thereby reversing its detrimental effects on the TME. Studies have shown that curcumin can reduce the number of M2 macrophages and increase the proportion of M1 macrophages by inhibiting the STAT3 signaling pathway, thereby restoring anti-tumor immune responses [19]. In addition to affecting immune cells, curcumin can directly target tumor cells by inhibiting STAT3-mediated proliferation and survival signals, thus slowing down tumor growth. When combined with existing cancer immunotherapies, such as immune checkpoint inhibitors, curcumin may further enhance the efficacy of these therapies by modulating immune cell function in the TME and strengthening the overall anti-tumor effect. A study using the Caco-2 cell line observed that curcumin treatment significantly reduced the expression of IL-4-induced M2 macrophage markers and decreased the secretion of anti-inflammatory cytokines, suggesting that curcumin has the potential to reverse M2 polarization [20]. Another animal model study showed that mice treated with curcumin exhibited lower tumor burden and a higher M1/M2 ratio, accompanied by a stronger anti-tumor immune response [21]. In summary, curcumin, by regulating the STAT3 signaling pathway, not only inhibits tumor growth but also enhances the body’s anti-tumor immune response by remodeling the immune cell composition in the TME. These findings provide strong scientific evidence for the potential of curcumin as an adjunctive anti-cancer therapy.

5 Effects of curcumin on cytokine regulation

Curcumin may influence the production and release of cytokines in BC cells and their surrounding microenvironment. It can modulate the balance of cytokines such as interferon-gamma (IFN-γ) and IL-2, which play a crucial role in regulating immune responses and anti-tumor effects. Dourado et al. [22] demonstrated that Th17 cells play a crucial role in promoting immune responses against extracellular pathogens by recruiting neutrophils and inducing inflammation. These cells produce inflammatory cytokines, such as TNF-α, IL-21, IL-17A, IL-23, IL-17F, IL-22, and IL-26. Curcumin has been shown to significantly inhibit the proliferation of Th17 cells and reduce the production of inflammatory cytokines, including TNF-α, IL-22, and IL-17 [23]. Figure 3 illustrates the multiple pathways through which curcumin regulates cytokines and immune responses. The pathways mainly include anti-inflammatory and pro-apoptotic pathways. Curcumin can inhibit the inflammatory response, specifically by suppressing the expression of cytokines such as TNF-α, IL-6, IL-1β, and TNF receptor-associated factor 6 (TRAF6). Additionally, curcumin can downregulate the growth hormone signaling pathway and inhibit Th17 cell proliferation, further highlighting its regulatory role in these aspects. The pro-apoptotic pathway involves the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated signaling pathways, which promote tumor cell apoptosis. Overall, curcumin influences the production and release of cytokines through various pathways, thereby regulating immune responses and promoting tumor cell apoptosis through complex mechanisms.

Figure 3

Multiple pathways of curcumin in regulating cytokines and immune responses.

6 Regulation of the TME by curcumin

The TME refers to the intricate milieu surrounding tumor cells, comprising a complex interplay of cellular and non-cellular components, including cells, extracellular matrix, vascular systems, immune cells, and chemical factors. Curcumin can modulate immune cells, cytokines, and signaling molecules within the TME, thereby influencing the immune response in BC. It can attenuate inflammatory responses and tumor-associated cytokine production, while enhancing immune cell functionality and activity, ultimately inhibiting tumor growth and metastasis. Research indicated that curcumin can augment the quantities of cluster of differentiation 4-positive (CD4+) T cells, cluster of differentiation 8-positive (CD8+) T cells, and IFN-γ within the TME, thereby enhancing their immune cytotoxic capabilities against tumor cells, while concurrently reducing cluster of differentiation 25 (CD25), regulatory T cells, and inflammatory cytokine levels, bolstering immune responsiveness and restoring immune surveillance capacity [24]. Cancer-associated fibroblasts (CAFs) secrete growth factors such as fibroblast growth factor, TGF-β, and vascular endothelial growth factor (VEGF), which promote tumor cell proliferation, angiogenesis, invasion, and metastasis. Studies suggest that curcumin can specifically target CAFs, thereby diminishing the invasiveness of pancreatic cancer cells [25]. Studies showed that curcumin can induce the polarization of TAMs from the pro-tumor M2 phenotype to the anti-tumor M1 phenotype. Curcumin promotes macrophage polarization toward the M1 phenotype by activating the AMP-activated protein kinase (AMPK) signaling pathway, which reduces the proliferation and migration of BC cells [26].

7 Effects of curcumin on tumor angiogenesis

Curcumin can impede the process of angiogenesis, thereby reducing the nutrient supply and growth of BC cells. It can disrupt tumor-associated angiogenic pathways, such as inhibiting the production of VEGF and suppressing signaling cascades involved in angiogenesis. VEGF is a glycoprotein that stimulates vascular growth, acting on receptors located on endothelial cell surfaces, such as VEGF receptor 1 (VEGFR-1) and VEGF receptor 2 (VEGFR-2), to induce endothelial cell proliferation and migration, ultimately leading to neovascularization. Overexpression of VEGF results in the formation of aberrant blood vessels, supplying ample nutrients to tumors and fostering tumor growth and metastasis. Research indicated that curcumin can inhibit VEGF expression by impeding proteases involved in the degradation of vascular basement membrane and extracellular matrix, thereby preventing the generation and dissemination of new tumor-associated blood vessels [27]. Furthermore, studies demonstrated that the combined use of curcumin and Astragalus polysaccharides can induce normalization and sparse remodeling of tumor vasculature morphology [28].

8 Research and adoption of curcumin as a therapeutic approach for BC

Conventional therapeutic approaches for BC include surgical intervention, radiotherapy, and chemotherapy. In non-conventional scenarios, endocrine therapy, targeted therapy, and immunotherapy are also employed. However, each of these approaches presents certain limitations in clinical practice. Curcumin, as a natural compound, exhibits remarkable potential in cancer therapy, underscoring its substantial promise as an alternative or adjunctive treatment for BC.

9 Conclusion

Curcumin, a natural compound, exhibits broad-spectrum anti-cancer activity and shows potential immune-modulatory effects. It influences immune responses through various mechanisms, including the regulation of immune cell functions, alteration of the TME, and modulation of immune cell activity. Its unique immune-regulatory properties enable curcumin to enhance the effects of immune cells on cancer cells, significantly inhibiting cancer cell proliferation, inducing autophagy, regulating the cell cycle, and promoting apoptosis. The low water solubility and rapid metabolism of curcumin limit its ability to maintain effective concentrations in vivo. Although novel delivery systems, such as nanotechnology and liposomal encapsulation, offer potential solutions, further validation is required before clinical application. Future research should focus on developing more effective delivery systems to overcome bioavailability issues, formulating personalized dosing regimens based on individual differences, and gaining a deeper understanding of the specific mechanisms of action of curcumin, particularly in terms of how it selectively affects tumor cells without damaging normal tissues. Additionally, larger-scale and long-term studies are needed to ensure its safety and efficacy as a therapeutic option. Furthermore, exploring the interactions between curcumin and other existing anti-cancer drugs or immune checkpoint inhibitors to identify optimal combination strategies could enhance therapeutic outcomes.