Natural compounds modulate the mechanism of action of tumour-associated macrophages against colorectal cancer: a review

Weichen Yuan; Jiexiang Zhang; Haibin Chen; Yupei Zhuang; Hongli Zhou; Wenting Li; Wenli Qiu; Hongguang Zhou

doi:10.1007/s00432-024-06022-8

. 2024 Nov 15;150(11):502. doi: 10.1007/s00432-024-06022-8

Natural compounds modulate the mechanism of action of tumour-associated macrophages against colorectal cancer: a review

Weichen Yuan ^1,^2,^#, Jiexiang Zhang ^3,^4,^#, Haibin Chen ^5,^#, Yupei Zhuang ^1,², Hongli Zhou ⁶, Wenting Li ^2,^✉,^#, Wenli Qiu ^7,^✉,^#, Hongguang Zhou ^1,^2,^✉,^#

PMCID: PMC11568041 PMID: 39546016

Abstract

Colorectal cancer (CRC) exhibits a substantial morbidity and mortality rate, with its aetiology and pathogenesis remain elusive. It holds significant importance within the tumour microenvironment (TME) and exerts a crucial regulatory influence on tumorigenesis, progression, and metastasis. TAMs possess the capability to foster CRC pathogenesis, proliferation, invasion, and metastasis, as well as angiogenesis, immune evasion, and tumour resistance. Furthermore, TAMs can mediate the prognosis of CRC. In this paper, we review the mechanisms by which natural compounds target TAMs to exert anti-CRC effects from the perspective of the promotional effects of TAMs on CRC, mainly regulating the polarization of TAMs, reducing the infiltration and recruitment of TAMs, enhancing the phagocytosis of macrophages, and regulating the signalling pathways and cytokines, and discuss the potential value and therapeutic strategies of natural compounds-targeting the TAMs pathway in CRC clinical treatment.

Keywords: Colorectal cancer, Tumour-associated macrophages, Mechanism of action, Natural compounds, Review

Introduction

Colorectal cancer (CRC) ranks as the third most prevalent form of cancer on a global scale. As per the GLOBOCAN database, there were an estimated 1.93 million fresh instances of CRC and 940,000 fatalities attributed to this disease worldwide in 2020. Furthermore, it is anticipated that by the year 2040, the incidence of new cases and mortality rates related to CRC will escalate to 3.2 million and 1.6 million, respectively (Sung et al. 2021; Morgan et al. 2023). The emergence of CRC is intricately linked to a multitude of factors, encompassing age, body weight, dietary patterns, gender, ethnicity, and physical activity levels (Siegel et al. 2023; Gonzalez-Gutierrez et al. 2024). The pathogenesis of CRC is also diverse, among which gene mutations, inflammatory effects, and immune regulation are important pathogenic mechanisms of CRC (Kim and Bodmer 2022). The development of CRC is driven by nutrient depletion and dysregulated cellular metabolism. When homeostatic growth factor signalling is absent, perturbations in oncogenes and oncogenes lead to metabolic adaptations that enable CRC cells to sustain their biomass and energy needs for proliferation (Sedlak et al. 2023). Intestinal inflammation has the potential to impact the barrier function of intestinal epithelial cells, thereby inducing DNA damage and instigating mutations that contribute to the initiation and development of CRC cells (Schmitt and Greten 2021; Shah and Itzkowitz 2022). For example, the inflammatory mediator interleukin-1α (IL-1α) promotes CRC progression (Cheng et al. 2021). The dysregulation of microbes has the potential to induce chronic inflammation and genetic modifications in the cells of the host. Simultaneously, the accumulation of immune cells and inflammatory factors creates a multifaceted chronic inflammatory milieu within the intestinal mucosa. Consequently, this environment may trigger oxidative stress or DNA damage in the epithelial cells, thereby facilitating the progression of CRC (Alrahawy et al. 2022; Yin et al. 2023).

The conventional treatment modalities for CRC encompass surgery, chemotherapy, and radiotherapy (Dekker et al. 2019; Jin et al. 2024). In terms of surgical modalities, laparoscopic CRC surgery is developing rapidly, and single incision laparoscopic surgery (SILS) combined with high safety robotic surgery is the future development trend (Jia et al. 2022; Baek et al. 2021). Chemotherapy is frequently employed for the management of intermediate and advanced CRC, encompassing diverse approaches such as preoperative neoadjuvant chemotherapy, intraoperative and postoperative chemotherapy, and palliative chemotherapy. Radiotherapy is widely employed as the primary treatment modality for anti-CRC therapy, particularly in cases of rectal cancer, and is regarded as the standard adjuvant treatment for patients with progressive rectal cancer (Pathak et al. 2023; Wang et al. 2023a). The advent of targeted and immunotherapy in recent years has greatly improved the treatment of CRC (Tjader and Toland 2024; Singh et al. 2024). Targeted agents, including the epidermal growth factor receptor (EGFR) inhibitor, the vascular endothelial growth factor (VEGF) inhibitor and the human epidermal growth factor receptor 2 (HER2) inhibitor, have demonstrated substantial improvements (Ohishi et al. 2023; Suwaidan et al. 2022; Napolitano et al. 2024). The identification of novel targets, including BRAF V600E mutations, NTRK gene fusions, and KRAS (G12C) mutations, has prompted the development of targeted drugs currently (Wong et al. 2023). The consistent utilisation of monoclonal antibodies, tumour vaccines, and immune factors has demonstrated promising prospects for the therapy of cancer (Fan et al. 2021; Johdi and Sukor 2020). Several programmed death 1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors have received approval for utilisation in the treatment of CRC (Payandeh et al. 2020). Although many of these modalities have achieved remarkable results, they are still accompanied by problems such as drug resistance and toxic side effects, and therefore new therapeutic strategies need to be found.

Natural compounds have demonstrated anti-CRC effects. For instance, curcumin has been observed to impede the propagation, motility, and transplantation of CRC cells by exerting substantial inhibitory effects on metastasis-associated in colon cancer 1 (MACC1) expression and MACC1-induced phenotypes (Gullu et al. 2022; Chen et al. 2021a). Additionally, multiple compound components of plants and animals have been shown to suppress CRC cell multiplication and metastasis by modulating various signalling pathways such as phosphatidylinositol 3-kinase (PI3K)/protein kinase-B (Akt), nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), and Wnt/β-catenin (Chen et al. 2023). These pathways hold promise as novel targets for CRC therapy. In recent years, targeting tumor-associated macrophages (TAMs) for CRC has good prospects and can better reflect the treatment effect and prognosis of CRC (Wang et al. 2021a).Also natural compounds can effectively treat CRC, so we linked natural compounds and TAMs to explore new ways to treat CRC. We have not found any articles on natural compounds-targeted TAMs for CRC, so we make a review, referring more to the studies in the last 5 years. This article first reviews the promotional effects of TAMs on CRC and then explores the mechanisms by which natural compounds target TAMs for the treatment of CRC.

TAMs and TME

The tumour microenvironment (TME) encompasses various components, including fibroblasts, immune cells, vascular endothelial cells, and the extracellular matrix (ECM), upon which tumour cells rely (Arneth 2019; Yu et al. 2024). Interactions between tumour cells and TME significantly impact tumour cell development, progression, and metastasis (Canellas-Socias et al. 2024). Tumour cells can modulate the TME by releasing signalling molecules that facilitate tumour angiogenesis and induce immunosuppression, whereas immune cells within the TME can influence tumour cell proliferation and metastasis (Xiao and Yu 2021). Immune cells present in TME can be categorised as innate immune cells, such as TAMs, dendritic cells, neutrophils, myeloid-derived suppressor cells (MDSCs), natural killer cells, and mast cells, whereas adaptive immune cells are mainly classified into T and B lymphocytes (Hinshaw and Shevde 2019; Li et al. 2020a). TAMs represent the most abundant subset of immune cells infiltrating the TME. These TAMs originate from bone marrow mononuclear cells and are recruited to the tumour site through the action of various chemokines (Yan and Wan 2021; Qin et al. 2023; Yue et al. 2024). Macrophages exhibit plasticity, wherein undifferentiated macrophages (M0) can differentiate into the classically activated M1 phenotype upon stimulation by factors produced by T helper cell type 1 (Th1), such as interferon γ (IFN-γ), tumour necrosis factor-α (TNF-α), lipopolysaccharide (LPS), and Toll-like receptors (TLR) (Shapouri-Moghaddam et al. 2018). M1 TAMs possess characteristics related to antigen presentation, which lead to an increase in the expression of inducible nitric oxide synthase (iNOS) (Nath and Kashfi 2020). Additionally, they facilitate the release of pro-inflammatory factors such as TNF-α, IL-1, IL-6, IL-12, IL-23, and cyclooxygenase-2 (COX-2), thereby promoting an inflammatory response. These M1 TAMs also play a role in mediating cytotoxicity and exerting an anti-tumour effect (Gao et al. 2022; Pan et al. 2020). M2 TAMs undergo polarization in the TME due to the influence of Th2 cytokines IL-4 and IL-13; additionally, other cytokines like IL-10 can modulate M2 polarization by activating signal transducer and activator of transcription (STAT)-3 through the IL-10 receptor (IL-10R), and up-regulation of the expression of arginase-1 (Arg-1) is one of the features of polarization in M2 TAMs (Shapouri-Moghaddam et al. 2018; Boutilier and Elsawa 2021). Notably, the presence of M2 macrophage infiltration in CRC is positively associated with IL-10 expression levels (Zou et al. 2022). M2 macrophages are abundantly present in TAMs and release various anti-inflammatory factors to facilitate tumour progression. M2 TAMs have been classified into four distinct subtypes, with the M2a subtype commonly linked to tissue fibrosis, the M2b subtype involved in immune regulation, the M2c subtype associated with immunosuppression and tissue remodelling, and the M2d subtype promoting angiogenesis (Gao et al. 2022; Mantovani et al. 2004).

It can be seen that TAMs are divided into two main types, namely the M1 type, which exerts anti-tumour effects, and the M2 type, which promotes tumour development. The dominant of the TAMs is the M2 type, which secretes anti-inflammatory factors such as transforming growth factor-β (TGF-β) that can also promote tumour development. This suggests that TAMs as a whole promote tumour progression. The infiltration and recruitment of TAMs, the M2-type dominance of TAMs, and the related signalling pathways and cytokines regulated by TAMs can promote tumour progression. We plotted Fig. 1 to elucidate that TAMs promote tumour development in TME. At the same time, it is evident that TAMs play a crucial role in facilitating tumour advancement through various mechanisms (Cassetta and Pollard 2020; Chen et al. 2019). These mechanisms encompass the stimulation of angiogenesis and lymphangiogenesis via the secretion of VEGF, EGF and chemokines C-X-C chemokine ligand (CXCL)8/12, thereby promoting tumour proliferation (Pan et al. 2020). Additionally, TAMs regulate epithelial-mesenchymal transition (EMT) to facilitate metastasis and tumour infiltration while also releasing chemokines and matrix metalloproteinases (MMPs) such as MMP2 and MMP9 to enhance tumour metastasis and infiltration further (May et al. 2023; Kessenbrock et al. 2010; Li et al. 2022a). Moreover, TAMs contribute to the immune escape from tumour cells by producing immunosuppressive factors like IL-10 and TGF-β, which inhibit the activity of T cells and NK cells (Xiang et al. 2021). From the above, it can be seen that TAMs can promote tumour progression through a variety of specified mechanisms such as promoting tumour proliferation, invasion, metastasis, angiogenesis, immune escape, etc., which provides reference and insights into the mechanism of action of TAMs in promoting CRC progression.

Fig. 1 — TAMs promote tumour development in TME. Figure depicts the role of macrophages in the tumour microenvironment and how they are polarized. Macrophages can either exert anti-tumor effects or promote tumour growth and metastasis. Tumour cells attract monocytes and other immune cells to the tumour microenvironment by releasing chemokines such as CCL2/CSF1/CXCL1, followed by differentiation of monocytes into M0 macrophages. On the one hand, M0 macrophages are activated to become M1 macrophages by LPS, GM-CSF, and IFN-γ/TNF-α secreted by Th1 cells; their cell surface produces CD80/CD86, COX-2, and MHC II, and cytokines such as TNF-α, iNOS, IL-6, and IL-12, which contribute to the antitumour response. On the other hand, M0 macrophages were induced to become M2 macrophages by IL-10, TGF-β, M-CSF, as well as IL-4 and IL-13 secreted by Th2 cells; their cell surfaces were able to produce CD163, CD206, and Arg-1, as well as to secrete IL-10, IL-12, and TGF-β and promote the proliferation and metastasis of tumor cells. In addition, there are four subtypes of M2 macrophages, of which M2a is activated by IL-4 and IL-13, which promotes tissue fibrosis and remodeling; M2b is activated by immune complexes and TLR, which allows immunomodulation; M2c is activated by IL-10 and TGF-β, which can exert phagocytosis; and M2d is activated by adenosine, which produces VEGF to promote angiogenesis. TAMs, tumour-associated macrophages; CCL, CC-chemokine ligand; CSF1, colony stimulating factor 1; CXCL, C-X-C chemokine ligand; Th, T helper cell type; IFN-γ, interferon γ; TNF-α, tumour necrosis factor-α; LPS, lipopolysaccharide; GM-CSF, granulocyte–macrophage colony stimulating factor; COX-2, cyclooxygenase-2; MHC II, major histocompatibility complex II; iNOS, inducible nitric oxide synthase; IL, interleukin; TGF-β, transforming growth factor-β; M-CSF, macrophage-colony stimulating factor; Arg-1, arginase-1; IC, immune complex; TLR, Toll-like receptors; GC, glucocorticoid; VEGF, vascular endothelial growth factor; MMPs, matrix metalloproteinases

TAMs contribute to CRC

Starting from the property of TAMs to promote tumour development, we next summarised the specific mechanisms of their role in promoting CRC development, with the literature dominated by studies from the last 5 years. The study indicated that TAMs were crucial in promoting CRC by facilitating pathogenesis, proliferation, invasion, metastasis, angiogenesis, immune evasion, drug resistance, and influencing CRC prognosis. TAMs promoted CRC through the seven specific mechanisms described above.

TAMs modulate CRC pathogenesis

TAMs, being the predominant population of immune infiltrating cells within the TME, have the capability to initiate CRC pathogenesis. The pathogenesis of CRC caused by smoking may be attributed to the infiltration of TAMs. Smoking-induced immunosuppression hampers macrophage phagocytosis and promotes the activity of M2-type macrophages. The correlation between smoking and the prevalence of CRC becomes more significant in the presence of low stromal macrophage counts (Ugai et al. 2022). Additionally, chronic inflammation over an extended period can result in colitis-associated carcinogenesis (CAC), and intestinal macrophages play an important role in CAC (Dong et al. 2022). Accumulation of CD163⁺ macrophages in adenomatous crypts and polarization of M2 TAMs can lead to CAC (Chiang et al. 2021). The downregulation of NF-κB activator 1 (Act1) in macrophages activates STAT3, subsequently facilitating the transformation of intestinal adenoma to adenocarcinoma (Wang et al. 2023b). Additionally, studies have demonstrated that in adenomatous polyposis coli (Apc)^Min/+ mice, a high-fat diet induces intestinal dysbiosis and accelerates the progression of intestinal adenomas to adenocarcinomas. This acceleration is achieved through the activation of the monocyte chemoattractant protein 1 (MCP-1)/CC chemokine receptor 2 (CCR2) axis, which leads to the recruitment and polarization of M2 TAMs (Liu et al. 2020a).

It can be seen that TAMs not only interact with CRC pathogenic factors such as smoking, but also regulate pathogenic mechanisms such as inflammatory and cancerous transformation and polarization of M2 TAMs, contributing to the pathogenesis of CRC from a variety of aspects such as etiology and pathogenesis. However, it is worth noting that in inflammatory bowel disease to CAC, the increase in proinflammatory factors should be proportional to the increase in M1-type macrophages, and the ideal outcome should be anticancer rather than pro-carcinogenic, but the true outcome is not, and the proinflammatory factors promote the progression from adenoma to adenocarcinoma. This suggests a complex bidirectional regulatory relationship between pro-inflammatory, anti-inflammatory factors, M1 TAMs and M2 TAMs, and a variety of pro-carcinogenic pathways, which are not purely M1-type pro-inflammatory (anti-cancer) and M2-type anti-inflammatory (pro-carcinogenic) relationships, but may involve multiple pathways or multiple pro-carcinogenic mechanisms.

TAMs promote CRC proliferation

Cell proliferation is a highly regulated biological process, whereas cancer cells exhibit uncontrolled cell proliferation. TAMs possess the ability to secrete and express various cytokines, including TGF-β, VEGF, platelet-derived growth factor (PDGF), and IL-6, among others, which play a crucial role in promoting CRC proliferation (Fasano et al. 2024). Within CRC tumour tissues and peripheral blood macrophages, TAMs contribute to CRC proliferation by releasing TGF-β1, which causes the downregulation of miR-34a and the upregulation of VEGF (Zhang et al. 2018). Additionally, TAMs-derived matrix metalloproteinase MMP1 significantly enhances colon cancer cell proliferation by facilitating the transition of the cell phase from G0/G1 to S and G2/M stages (Yu et al. 2021). The HIF-prolyl hydroxylases PHD1, PHD2, and PHD3 are crucial in regulating cellular adaptation to hypoxia. Specifically, the deficiency of PHD2 leads to an increased number of TAMs and the upregulation of the EGFR ligand epiregulin in macrophages. This, in turn, enhances the STAT3 as well as the extracellular signal-regulated protein kinase (ERK) 1/2 signalling pathways, ultimately promoting cell proliferation in colon cancer (Kennel et al. 2022).

The above studies confirmed that the proliferative effect of TAMs on CRC cells mainly involves a variety of cytokines and signalling pathways, which are most closely associated with growth factors, such as TGF-β, VEGF, EGFR, etc. This is also related to the mechanism of growth factors regulating cell growth and proliferation, but further exploration and improvement of the relevant mechanisms are still needed.

TAMs promote CRC invasion and metastasis

Studies have shown that EMT has an essential role in the metastatic cascade of carcinomas derived from epithelial cells (Sun et al. 2024). Additionally, the modulation of EMT in tumour cells and the polarization of TAMs into the M2-type by cytokines or exosomes contribute to promoting CRC metastasis (Han et al. 2021). On the one hand, EMT is an important cause of invasion and metastasis. TAMs promote EMT through the TGF-β/Smad2,3–4/Snail signalling pathway or by releasing TGF-β signalling, contributing to CRC from migration and invasion (Gazzillo et al. 2022; Cai et al. 2019). Furthermore, the Snail transcription factor promotes EMT and subsequent secretion of CXCL2 by mesenchymal tumour cells, thereby facilitating the infiltration of M2-type macrophages and promoting lung metastasis in CRC (Bao et al. 2022). MMPs are another important effector molecule during EMT, and TAMs can promote endothelial cell migration by secreting a variety of MMPs (DeNardo et al. 2008). Interleukin-1β (IL-1β) induced up-regulation of serum amyloid A1 (SAA1) expression in CRC cells, which subsequently up-regulated MMP-9 in macrophages and promoted cell migration and invasion (Sudo et al. 2021). Additionally, the M2-type polarization of TAMs represents another noteworthy mechanism contributing to tumour cell invasion and metastasis. M2 TAMs induce CRC liver metastasis by secreting CXCL13, possibly involving the exosome miR-934 (Zhao et al. 2020a). The exosome circVCP promotes macrophage M2 polarization and inhibits M1 polarization through the miR-9-5p/Neuropilin 1 (NRP1) axis, facilitating CRC invasion and metastasis (Tang et al. 2023). Binding of cathepsin K (CTSK) to TLR4 stimulated M2 polarization and secretion of IL-10 and IL-17 from TAMs via the mammalian target of rapamycin (mTOR) pathway, which in turn promoted CRC invasion and metastasis via the NF-κB pathway (Li et al. 2019). Elevated Transcription Factor 4 promotes the interaction of CRC cell-derived CC-chemokine ligand 2 (CCL2) with CCR2 to modulate infiltration and M2 polarization of tumour TAMs, facilitating CRC invasion and metastasis (Tu et al. 2021). CXCL1 is found to be overexpressed in CRC tissues and its activation of NF-κB/P300 facilitates the migration of M2 TAMs, while also disrupting the aggregation of CD4⁺ and CD8⁺ T cells at the tumour site and promoting the migration of colon cancer cells (Zhuo et al. 2022). The secretion of cytokines by TAMs plays a pivotal role in regulating key pathways that facilitate CRC invasion and metastasis. TAMs contribute to the glycolytic state of CRC, and TAMs produce TGF-β to support Hypoxia-inducible factor-1α (HIF-1α) expression, which upregulates the activation of the Tribbles Pseudokinase 3 (TRIB3)-mediated β-catenin/Wnt signalling pathway, and ultimately enhances CRC invasion (Liu et al. 2021).

It follows that the promotion of CRC invasion and metastasis by TAMs is the most common mechanism of CRC development and has been most clearly studied. It can be seen that the promotion of invasion and metastasis by TAMs is evident through various mechanisms, including EMT, polarization towards M2-type macrophages, and regulation of invasion- and metastasis-related cytokines and pathways. These mechanisms synergistically contribute to the overall effect of TAMs in facilitating invasion and metastasis.

TAMs promote CRC angiogenesis

TAMs have the ability to secrete various cytokines, including VEGF, EGF, PDGF, TNF-α, TGF-β, IL-1/8, and MMPs, to facilitate tumour neovascularisation for tumour progression. Previous research has demonstrated a positive correlation between the density of TAMs and the extent of neovascularization (Shibutani et al. 2021). Angiogenesis regulators play a crucial role in angiogenesis, and three specific regulators, namely S100A4, SPP1, and SPARC, are expressed in CD68⁺ TAMs and are primarily associated with the stromal component, particularly in macrophages (Kazakova et al. 2023). TNF-α promotes tumour angiogenesis, whereas the use of anti-TNF-α monoclonal antibody acts as a tumour suppressor, impeding angiogenesis in models of inflammatory carcinoma and CRC subcutaneous grafts (Takasago et al. 2023). Another study showed that the expression of VEGFR2 in CRC M2 TAMs was significantly higher than in normal mucosa and that there was a significant correlation between mRNA expression of VEGFR2 (KDR) and the characteristics of M2 TAMs, and that cytokine in vitro-induced production of TGF-β1 by M2 macrophages through the VEGF/VEGFR2 signalling pathway (Min et al. 2021). And TGF-β1 can promote tumour angiogenesis.

It can be seen from the above that TAMs can promote angiogenesis in tumour cells, and a variety of angiogenesis regulators can be produced by TAMs or highly expressed in M2 TAMs, and perhaps anti-angiogenic drugs can also effectively inhibit the pro-CRC effects of TAMs. Meanwhile, the phenotype of TAMs is also closely related to angiogenesis regulators, and it is possible to try to change the phenotype of TAMs to verify their potentiating effect against CRC angiogenesis. Induction of polarization of M2-type TAMs to M1-type TAMs in combination with anti-angiogenic drugs may exert a good synergistic effect.

TAMs promote immune escape from CRC

TAMs use immune-editing mechanisms in the TME to regulate the TME into a tumour-suppressive or progressive environment, where tumour cells construct an immunosuppressive microenvironment in which TAMs can polarise from M1-type macrophages to M2-type, thereby promoting CRC immune escape and tumour progression (Cheruku et al. 2023). Immune cells depend on amino acid metabolism for energy and biomass, and the absence of ACADS, a key enzyme for amino acid metabolism in colonic TAMs, polarises TAMs into M2 macrophages, leading to immune escape from CRC (Jiang et al. 2022; Dussold et al. 2024). There was marked immunosuppression of TME in patients with CRC liver metastases, with high expression of MDSC signature genes, mannose receptor C-type 1 (MRC1), and genes related to M2 TAMs, a marked upregulation of the number of M2 TAMs, and depletion of the T-cell population, with a concomitant significant increase in the CD4⁺ T-cell population and a decrease in the CD8⁺ T-cell population (Geng et al. 2022). The pro-lymphangiogenic factor VEGFC, which is abundant in CRC, promotes tumour immune escape by activating TAMs and VEGFR3 on lymphatic vessels (Tacconi et al. 2019). TAMs express PD-1/PD-L1, a pathway that plays a key role in the immune escape of tumour cells. Blocking the PD-1/PD-L1 signalling pathway reduces the ratio of regulatory T cells (Tregs), MDSCs and TAMs in the tumour microenvironment, enhances T cell killing activity and inhibits CRC growth (Zhang et al. 2020a). The transmembrane protein MS4A4A is selectively highly expressed in TAMs and activates the PI3K/AKT and Janus Kinase (JAK)/STAT6 pathways to promote M2 polarization of macrophages to induce tumour cell immune escape; MS4A4A blockade therapy remodelled the tumour immune microenvironment, diminishing infiltration of M2-TAMs and failing T-cells, and enhancing infiltration of effector CD8⁺ T-cells, and anti-MS4A4A therapy may improve the efficacy of ICIs such as PD-1 therapy in CRC (Li et al. 2023).

From the above, it can be seen that the M2-type differentiation of TAMs is the main cause of tumour immune escape, whereas M2 TAMs can promote immune escape by achieving T-cell depletion, especially CD8 ⁺ T-cell reduction, through signalling pathways such as PD-1/PD-L1 and PI3K/AKT. Among them, the PD-1/PD-L1 pathway is the main pathway responsible for immune escape, so blocking the PD-1/PD-L1 pathway might inhibit TAMs-induced immune escape. Research could also be focused on the mechanism of interaction between CD8 ⁺ T cells and TAMs cells to improve the immune escape of CRC tumour cells.

TAMs promote treatment resistance in CRC

TAMs can lead to resistance to chemotherapy, radiotherapy, targeted therapy and immunotherapy for CRC. TAMs can lead to inefficient drug distribution to CRC cells through angiogenesis, resulting in chemoresistance (Shibutani et al. 2021). Macrophages specifically overexpress dihydropyrimidine dehydrogenase (DPD) under hypoxic conditions, leading to macrophage-induced 5-fluorouracil (5-FU) chemoresistance in CRC through drug inactivation, and DPD expression is controlled by HIF-2α (Malier et al. 2021). ROS induced during CRC chemotherapy activated HIF-1α signalling, further driving HMGB1 expression, which promoted infiltration of TAMs, leading to the development of 5-FU chemoresistance, while high levels of GDF15 produced by TAMs impaired chemo-sensitivity of tumour cells through enhanced fatty acids β-oxidation (Zheng et al. 2021). One study showed that although 5-FU suppressed tumour growth, 5-FU enriched cancer stem cells (CSCs) through the Wnt/β-catenin signalling pathway promoted infiltration of TAMs through the NF-κB signalling pathway and improved EMT through the STAT3 signalling pathway, which led to chemoresistance, hence the need to reduce the number of CSCs, inhibit infiltration of TAMs and progression of EMT (Su et al. 2023). Also, in the CT26 mouse model, blockade of CCL2 reduced TAMs recruited into the TME and altered tumour perfusion during early response to tumour therapy, with reduced chemoresistance to 5-FU (Bess et al. 2022). Another study found that oxaliplatin (OXA)-resistant patients had a significantly higher density of infiltrating macrophages in CRC tissues, with an increase in the total N⁶-methyladenosine (m⁶A) RNA content and the expression of its key methyltransferase METTL3, and that M2 TAMs increased OXA resistance by enhancing METTL3-mediated modification of m⁶A in the cells; this study revealed that M2 TAMs are an essential mediator in the acquisition of important mediators of OXA resistance, and targeting M2 TAMs and METTL3-mediated m⁶A modifications may be a therapeutic approach for OXA resistance (Lan et al. 2021; Liu et al. 2024; Zhang et al. 2024). In addition to this, another study also found that increasing the infiltration of TAMs in tumour tissue can reduce the efficacy of bevacizumab combination chemotherapy in patients with advanced CRC (Dost Gunay et al. 2019). Also, in CRC patients treated with FOLFOX, the drug polarised macrophages from M2 to M1 type, increasing the sensitivity of chemotherapy to some extent (Cavalleri et al. 2022).

These results suggested that TAMs could promote drug resistance in CRC, which might be related to the hypoxic environment, or ROS related to oxygen metabolism. Therefore, pathways such as hypoxia and oxidative stress may be involved in the mechanism of TAMs-induced drug resistance, which can be further explored. At the same time, the resistance can be reversed by M1 polarization, etc. And the above studies mainly focus on the resistance mechanism of chemotherapy, but also need to further explore the resistance mechanism of TAMs with targeted therapy, radiotherapy and immunotherapy in CRC, and more experiments can be carried out in the relevant direction in the next step.

TAMs mediate prognosis in CRC

CD68 is a pan-macrophage marker, CD11c and CD80 are markers for M1 macrophages, and CD163 is the best marker for M2 macrophages (Liu et al. 2013; Pinto et al. 2019). A study showed that among 148 patients with CRC who underwent surgical resection, patients with high levels of CD11c-positive macrophage infiltration had longer overall survival (OS), a high proportion of CD68-positive macrophages could represent distant metastases, infiltration of CD68- and CD163-positive macrophages predicted poorer OS, and a high proportion of CD68- and CD163 positive macrophages were linked to good Disease-free survival (DFS) (Shin et al. 2021). In 419 cases of tumour invasive front (TF) of CRC tissues, CD68_TF⁺ macrophages impeded EMT and CSC production, induced adaptive immune responses, and improved OS in CRC patients; thus, high CD68⁺ macrophage infiltration was a favourable prognostic factor for patients (Li et al. 2018a). After processing 150 CRC cases by immunohistochemistry, the results showed a predominance of M2 TAMs, CD80⁺ macrophages mainly were distributed on matched tumours adjacent normal mucosa (ANM) and predominated in less invasive stage T1 tumours, CD163⁺ macrophages were predominantly distributed in TF and were more prevalent in stage II tumours, and higher CD68 and lower CD80/CD163 ratio in phase III tumours represented a decrease in OS (Pinto et al. 2019). CRC tumour cell-induced PD-L1⁺CD206⁺ macrophage subsets correlate with poor prognosis (Yin et al. 2022). Algars A et al. investigated the prognostic role of CD68⁺ and CLEVER-1⁺ (common lymphatic endothelial and vascular endothelial receptor 1) TAMs in 498 patients with stage I-IV CRC and early stage I CRC and younger patients, the High numbers of CD68⁺ and CLEVER-1⁺ TAMs were associated with disease-specific survival (DSS). In contrast, high intratumoral CLEVER-1⁺ macrophage numbers in stage IV disease were detrimental to DSS (Algars et al. 2021). Colony-stimulating factor 1 receptor, a proto-oncogene, is highly expressed in TAMs of CRC patients, suggesting a poor prognosis (Zhu et al. 2022). It has been noted that large numbers of CD206 TAMs (tumours with high M2 density) are positively correlated with recurrence-free intervals, suggesting that increased M2 macrophage counts in the TME are more prognostically favourable for patients with CRC (Konstantinov et al. 2022). PD-1, PD-L1, IDO and TAMs in CRC liver metastases were correlated with less aggressive features and better prognosis in CRC patients (Takasu et al. 2021). The results of a study indicate that a high expression of CD86⁺ and CD68⁺ CD86⁺ TAMs and a low expression of CD163⁺ and CD68⁺ CD163⁺ TAMs were significantly associated with a favourable OS in CRC. Furthermore, the level of CD86 protein expression was found to be significantly and inversely correlated with tumour differentiation and tumour node metastasis (TNM) stage. Conversely, CD163 protein expression showed a significant and positive correlation with tumour differentiation and size. Therefore, the presence of high expression of CD86 TAMs suggested a positive prognosis, while high expression of CD68⁺ CD163⁺ TAMs indicated a poor prognosis (Kou et al. 2022). EMR1, belonging to the adhesion G protein-coupled receptor family (ADGRE1), serves as a marker for M2 macrophage polarization and exhibits abnormal expression in cancer cells. The presence of EMR1 in tumour cells (EMR1-TC) demonstrated a significant correlation with CD68⁺ CD163⁺ TAMs. Moreover, CRC patients with elevated EMR1-TC⁺ CD68⁺ CD163⁺ scores exhibited a diminished prognosis in terms of recurrence-free survival. Additionally, EMR1-TC was identified as a high-risk factor for lymph node metastasis and was associated with a poorer recurrence-free survival outcome (Akter et al. 2022). Patients with low expression of three M1 molecular markers (NOS2/CXCL10/CD11c) had lower OS, whereas patients with high expression of three M2 molecular markers (CD163/CD206/CD115) had lower OS rates (Wang et al. 2023c). The M2/M1 type macrophage ratio was also more predictive of the risk of CRC lymph node metastasis (Inagaki et al. 2021).

From the above, it can be seen that the phenotype of TAMs is an important marker affecting the prognosis of CRC, but it is still mostly judged by the typing of M1 versus M2 TAMs markers, i.e., a high proportion of M1 TAMs markers indicates a good prognosis, whereas a high proportion of M2 TAMs represents a poorer prognosis. Of course this is not absolute, and factors such as patient staging and type of pathology can also influence marker typing of TAMs, so typing of TAMs is not a completely accurate marker for mediating prognosis, but only provides a predictive possibility.

Treatment of TAMs and CRC

Since TAMs promote the occurrence and development of CRC, targeting TAMs for treating CRC has a broad prospect. Current anti-tumour therapeutic modalities for targeting TAMs mainly include inhibiting the recruitment and infiltration of TAMs, depleting TAMs, modulating the polarization of TAMs and regulating cytokines and signalling pathways associated with TAMs. For example, apple polysaccharide, purple yam polyphenol extracts, and tea polysaccharides exerted anti-inflammatory and anti-CRC effects by inhibiting the infiltration of TAMs (Liu et al. 2018; Yang et al. 2023; Li et al. 2020b). Litchi procyanidins inhibited the metastasis of CT26 colon cancer cells by decreasing the number of TAMs and inflammatory factors in TME (Yao et al. 2023). The active fraction of Garcinia yunnanensis (YTE-17) and Astragalus mongholicus Bunge–Curcuma aromatica Salisb. suppressed the progression of CRC cells by inhibiting the polarization of M2-type macrophages (Gu et al. 2022; Sui et al. 2020). Safflower polysaccharide did not directly inhibit the growth of CRC cells, but rather promoted M1 macrophage polarization by upregulating NF-κB signalling and releasing TNF-α and NO to induce CRC cell apoptosis (Wang et al. 2021b). In LPS-stimulated RAW 264.7 macrophages, a polyphenol-rich extract isolated from Pleurotus eryngii (PPEP) inhibited the overproduction of pro-inflammatory mediators, such as NO and ROS, and suppressed the expression of iNOS, p-IκB protein, as well as NF-κB and IκB mRNA, through inhibiting the overproduction of pro-inflammatory mediators such as NO and ROS to exert anti-inflammatory effects, while PPEP has the impact of blocking the cell cycle, inhibiting proliferation and promoting apoptosis in HCT116 colon cancer cells (Hu et al. 2018). In addition, polysaccharides from Nostoc commune Vaucher significantly activated mice macrophages through activation of the NF-κB and AKT/JNK1/2 signalling pathways, as evidenced by increased macrophage size and phagocytosis and increased TNF-α and IL-1β expression; meanwhile, the activated macrophages inhibited CRC cell proliferation and CRC tumour growth in mice (Guo et al. 2019). This shows that anti-CRC therapy for TAMs is promising and has outstanding efficacy.

Mechanisms of natural compounds targeting TAMs for CRC treatment

Natural compounds are metabolites with special activities isolated and extracted from animals, plants and microorganisms in nature, which have been used as medicines for thousands of years and are widely used in many Asian countries. Natural compounds are rich in materials, multiple targets and high in biological activity, and can play a preventive and therapeutic role in treating malignant tumours (Islam et al. 2022; Naeem et al. 2022). An increasing number of natural compounds have been shown to have antitumour activity, such as diphyllin (Li et al. 2022b), andrographolide (Zhang et al. 2021) and others. In the previous period, we found articles on natural compounds targeting TAMs for treating other cancers, such as lung cancer, through searching, and we did not find articles summarising and outlining CRC. Therefore, in this paper, from the promotion of TAMs on CRC, there are four specific mechanisms of natural compounds-targeted TAMs against CRC, which are regulating the polarization of TAMs, reducing the recruitment and infiltration of TAMs, enhancing phagocytosis of macrophages, and regulating the related cytokines and signalling pathways. We drew Fig. 2 to explain this relationship better. The molecular structural formulae of the compounds were also searched from Pubchem and Table 1 was set up for the mechanism of natural compounds targeting TAMs against CRC.

Fig. 2 — The specific mechanism of natural compounds targeting TAMs against CRC. The orange and yellow parts on the left side of the figure show the process of TAMs promoting the development of CRC. It can be seen that TAMs can promote angiogenesis, promote invasion and metastasis, promote proliferation, regulate pathogenesis, promote immune escape, promote treatment resistance and mediate prognosis in CRC. The cyan and blue parts on the right side of the figure show the pathways for targeting TAMs to treat CRC, which mainly include regulating TAMs polarization, decreasing TAMs infiltration and recruitment, increasing phagocytosis by macrophages, and regulating related signaling pathways and cytokines. CRC, Colorectal Cancer; TAMs, tumour-associated macrophages

Table 1.

Mechanisms of natural compounds targeting TAMs against CRC

Name	Source	Types of natural compounds	Modelling (natural compound administered dose)		Markers		Overall Mechanism	References
Name	Source	Types of natural compounds	In vivo	In vitro	In vivo	In vitro	Overall Mechanism	References
Dioscin C₄₅H₇₂O₁₆	Dioscorea nipponica Makino	Steroids	AOM/DSS mouse model (2.5, 5, 10 mg/kg)	BMDMs (0.5, 1 μM)	↑: iNOS ↓: Arg-1	↑: CD86⁺ cells, iNOS, TNF-α, IL-6, IL-1β ↓: Arg-1, Mrc1, CD206⁺ cells	Promotion of M1-type polarization and inhibition of M2-type polarization	Xun et al. (2023)
Nemorosone C₃₃H₄₂O₄	Cuban brown propolis	Ketones	–	THP-1 and HT-29 cells (5, 10, 25 and 50 µM)	–	↓: IL-8, IL-10, CCL2, CD206, VEGF genes	Inhibition of M2-type polarization	Frion-Herrera et al. (2020)
Vitexin C₂₁H₂₀O₁₀	Vitex negundo var. cannabifolia (Sieb.et Zucc.) Hand.-Mazz	Flavonoids	AOM/DSS mice (40, 160 mg/kg/d)	–	↑: IL-10, iNOS, ratio of CD68/CD206 protein ↓: TNF-α, IL-1β, IL-6	–	Inhibition of M1 polarization in inflammatory tissues and promotion of M1 polarization in tumour tissues	Chen et al. (2021b)
Triptolide C₂₀H₂₄O₆	Tripterygium wilfordii Hook. f	Terpenes	CT26 mice (0.1, 0.2 and 0.4 mg/kg)	HT29 and CT26 cells (0, 20, 40 and 80 nM)	↓: F4/80⁺ cells	↓: Arg-1, CD206, IL-10 genes	Inhibition of M2-type polarization	Jiang et al. (2021)
Triptolide C₂₀H₂₄O₆	Tripterygium wilfordii Hook. f	Terpenes	AOM/DSS mice (0.05, 0.2 mg/kg/d)	–	↓: CD206 gene, Activity of the SPHK-S1P signaling pathway	–	Inhibition of M2-type polarization	Li et al. (2020c)
Triptolide C₂₀H₂₄O₆	Tripterygium wilfordii Hook. f	Terpenes	AOM/DSS mice (0.05, 0.2 mg/kg/day)	THP-1 macrophages (5, 10 or 20 nM)	↓: Arg-1, CD206, CD204, CD163 genes	↓: Arg-1, CD206, CD204, CD163 genes	Inhibition of M2-type polarization	Li et al. (2020d)
Celastrol C₂₉H₃₈O₄	Tripterygium wilfordii Hook. f	Terpenes	APC^Min/+ mice (1 mg/kg)	HCT116 and SW480 cells (0.75 μM)	↑: CD16/32 protein ↓: CD206 protein	↑: iNOS protein ↓: Arg-1 protein	Promotion of M2-type polarization to M1-type	Wang et al. (2023d)
Quercetin C₁₅H₁₀O₇	Hippophae rhamnoides L	Flavonoids	–	HCT116 and LoVo cells ( −)	–	↓: CD163, CD206 cells	Inhibition of M2-type polarization	Chen et al. (2022)
Berberine C₂₀H₁₈NO₄⁺	Coptis chinensis Franch	Alkaloids	AOM/DCC mice (40 mg/kg)	BMDMs ( −)	↓: TNF-α, IL-1β, IL-6, NO, CD206⁺F4/80⁺ cells	↑: SOCS1 signaling ↓: IL-6, IL-1β, TNF-α, miR-155-5p gene	Inhibition of M1-type polarization	Ling et al. (2023)
Patchouli alcohol (PA) C₁₅H₂₆O Pogostone (PO) C₁₂H₁₆O₄	Pogostemon cablin	PA: Terpenes PO: Lipids	Apc^Min/+ mice (40 mg/kg/d)	–	↑: Arg-1 protein, Ym-1 protein, MR, IL-4, IL-10, IL-13, TGF-β ↓: iNOS, CXCL10, IFN-γ, IL-1β, IL-6, IL-12, IL-17, IL-18, TNF-α	–	Promotion of M1-type polarization to M2-type and remodelling of the inflammatory environment	Leong et al. (2022)
Cucurbitacin B C₃₂H₄₆O₈	Muskmelon pedicel	Terpenes	CT26 mice (0.5, 1 mg/kg)	RAW 264.7, THP-1H, CT116 and CT-26 cells ( −)	↓: CD206⁺ cells	↓: Ym-1, Fizz-1, Arg-1 proteins, IL-10, Activity of the JAK2/STAT3 signaling pathway	Inhibition of M2-type polarization	Zhang et al. (2022)
Bigelovin C₁₇H₂₀O₅	Inula helianthus-aquatica	Terpenes	Colon 26-M01 mice (0.3, 1 and 3 mg/kg) HCT116 mice (1 mg/kg)	–	↑: IFN-γ, IL-1β, IL-12 ↓: IL-4, IL-6/STAT3 signaling pathway		Promotion of M1-type polarization and inhibition of M2-type polarization	Li et al. (2018b)
Cannabidiol C₂₁H₃₀O₂	Cannabis plant	Terpenes	–	IL-4-stimulated BMDMs (10 μM)	–	↑: Expression of NOS2, CD86, Il12b genes ↓: CD206 protein, PI3K-Akt signaling pathway	Promotion of M2-type polarization to M1-type	Sun et al. (2023)
Bufalin C₂₄H₃₄O₄	Cinobufacini	Terpenes	CT26 mice (0.1, 0.5 mg/kg)	HCT116 and CT26 cells ( −)	↓: CD68, CD206 proteins, IL10, TGF-β	↓: CD11b⁺CD206⁺ cells, IL10, TGF-β, MIF	Inhibition of M2-type polarization	Chen et al. (2021c)
Gynostemma pentaphyllum (GP) C₄₇H₈₀O₁₇	Ganoderma lucidum (Curtis) P. Karst., Gynostemma pentaphyllum (Thunb.) Makino	Glycosides	Apc^Min/+ mice (300 mg/kg)	–	↑: Arg-1 protein, MR, Trem2, Ym-1 protein, IL-4, IL-10, IL12, IL-13 ↓: iNOS, CXCL10 protein, IFN-γ, IL-1β, TNF-α, FOXP3 protein	–	Promotion of M1-type polarization to M2-type	Khan et al. (2019)
Arabinogalactan (PTPS-1–2) C₂₀H₃₆O₁₄	Typha angustifolia L	Polysaccharides	–	RKO cells (0–400 μg/mL)	–	↑: NF-κB, iNOS, TNF-α, CD86 gene, CD16 gene	Promotion of M1-type polarization	Xu et al. (2023)
Gambogic Acid (GA) C₃₈H₄₄O₈	Garcinia hanburyi Hook.f	Xanthenes	CT26 mice (5 mg/kg)	–	↑: CD86⁺, IFN-γ⁺ CD8⁺ cells ↓: TGF-β⁺ CD206⁺ cells	–	Promotion of M2-type polarization to M1-type	Wang et al. (2023e)
β-Carotene C₄₀H₅₆	Daucus carota var. sativa Hoffm	Vitamins	AOM/DSS mice (5, 15 mg/kg)	U937 cells (20, 40 μM)	↓: CD206, Arg-1, Ym-1 genes, CD163, PPAR-g proteins	↓: Arg-1 gene, TGF-β1, CD163 protein, PPAR-g protein	Inhibition of M2-type polarization	Lee et al. (2020)
Palmitic acid C₁₆H₃₂O₂	Most of the plants and animals	Fatty acid	–	RAW 264.7 cells (10 μM)	–	↑: CD68 protein, IL-12 ↓: CD163 protein, IL-10	Promotion of M2-type polarization to M1-type	Araujo et al. (2020)
Piceatannol C₁₄H₁₂O₄	Euphorbia pekinensis Rupr	Benzene derivatives	SW480 mice (10, 50 mg/kg)	SW480 cells (25 μM)	↓: CD163 protein, TGF-β1	↓: TGF-β1	Inhibition of M2-type polarization	Chiou et al. (2022)
Mannose C₆H₁₂O₆	Cranberry, peach, apple	Monosaccharides	AOM/DSS mice (1000, 2000 mg/kg)	HCT116 cells (1, 3, 10 nM)	↓: CD206 protein, VEGF gene, Arg-1 gene and protein, HIF-1α gene and protein, HK II protein	↓: VEGF gene, Arg-1 gene and protein, HIF-1α gene and protein	Inhibition of M2-type polarization	Liu et al. (2022)
Ovatodiolide (OV) C₂₀H₂₄O₄	Anisomeles indica (L.) Kuntze	Terpenes	–	HCT116 and DLD-1 cells (14 μM)	–	↓: Arg-1, CD23 protein, YAP1 protein, NF-κB, Akt protein, IL-6	Inhibition of M2-type polarization	Huang et al. (2017)
2-Methylpyridine-1-ium-1-sulfonate (MPS) C₆H₇NO₃S	Allium macrostemon Bunge	Pyridines	-	THP-1 and HT-29 cells (2, 4 µM)	–	↑: CD80 protein ↓: PD-L1, TGF-β, TEX, CD163 protein, IL-10	Promotion of M1-type polarization and inhibition of M2-type polarization	Rastegari-Pouyani et al. (2022)
Astragaloside IV (AS-IV) C₄₁H₆₈O₁₄	Astragalus membranaceus (Fisch.) Bunge	Glycosides	CT26 mice (15 mg/kg)	IL-4-induced BMDMs (10, 50 and 100 nM)	↑: IFN-γ, IL-12, TNF-α, NOS2↓: TGF-β, IL-10, VEGFA, Arg-1, Mrc1 genes	↑: MHCII^hi macrophage, IL12, NOS2 ↓: CD206^hi macrophage, Arg-1, Mrc1 genes	Promotion of M2-type polarization to M1-type	Liu et al. (2020b)
Fucoidan C₇H₁₄O₇S	Laminaria japonica Aresch	Polysaccharide	HCT116 mice (200, 300 mg/kg/day)	RAW264.7, HCT116 and RKO cells (100, 200 μg/mL)	↑: CD86⁺ cells ↓: CD206⁺ cells	↑: NO, IL-6, TNF-α, CD86⁺ cells ↓: CD206⁺ cells	Promotion of M1-type polarization and inhibition of M2-type polarization	Deng et al. (2022)
15-Hydroxy-6α,12-epoxy-7β,10αH,11βH-spiroax-4-ene-12-one (HESEO) C₁₅H₂₂O₃	Avicennia marina (Forsk.) Vierh	Terpenoids	CMT-93 mice (0.1–62.5 µM)	–	↑: IFN-γ, CXCL9, TNF-α, IL-15 ↓: Ym-1, Arg-1	–	Promotion of M2-type polarization to M1-type	Zhao et al. (2020b)
4,4′-Dihydroxystilbene C₁₄H₁₂O₂	Yucca periculosa	Organic hydroxy compound	AOM/DSS mice (5 or 12.5 mg/kg)	–	↓: IL-1β, IL-6, MCP-1, VEGF, COX-2, PD-1	–	Inhibition of M2-type polarization	Kimura et al. (2020)
Macelignan C₂₀H₂₄O₄	Myristica fragrans Houtt	Lignans	Sw620 mice (100 μL every 3 days)	RAW264.7 and THP-1-derived macrophages (–)	Tumor growth was prevented	↓: Arg-1, CD206 protein, CD163 protein, p-PI3K, p-AKT, IL-1β, NF-κB p65 gene	Inhibition of M2-type polarization	Che et al. (2024)
Triptolide C₂₀H₂₄O₆	Tripterygium wilfordii Hook. f	Terpenes	CT26 mice (0.1, 0.2 and 0.4 mg/kg)	–	↓: F4/80⁺ cells	–	Reduction of infiltration of TAMs	Jiang et al. (2021)
Triptolide C₂₀H₂₄O₆	Tripterygium wilfordii Hook. f	Terpenes	AOM/DSS mice (0.05, 0.2 mg/kg/d)	–	↓: CD68 protein	–	Reduction of infiltration of TAMs	Li et al. (2020c)
Triptolide C₂₀H₂₄O₆	Tripterygium wilfordii Hook. f	Terpenes	AOM/DSS mice (0.05, 0.2 mg/kg/day)	–	↓: CD68, MCP-1 genes	–	Reduction of infiltration of TAMs	Li et al. (2020d)
Dihydroisotanshinone I (DT) C₁₈H₁₄O₃	Salvia miltiorrhiza Bunge	Phenanthrenes	–	RAW 264.7 cells (5/10 μM)	–	↓: CCL2 protein	Reduction of recruitment of TAMs	Lin et al. (2017)
Emodin C₁₅H₁₀O₅	Rheum palmatum L., Polygonum cuspidatum Sieb.et Zucc., Pleuropterus multiflorus (Thunb.) Nakai	Anthraquinones	AOM/DSS mice (40, 80 mg/kg)	–	↑: NOS2 ↓: CD206⁺ cells, P2X7, STAT3 signaling	–	Reduction of recruitment of TAMs	Sougiannis et al. (2022)
Emodin C₁₅H₁₀O₅	Rheum palmatum L., Polygonum cuspidatum Sieb.et Zucc., Pleuropterus multiflorus (Thunb.) Nakai	Anthraquinones	AOM/DSS mice (50 mg/kg)	RAW 264.7 macrophages (10, 20 and 40 mM)	↓: CD11b⁺, F4/80⁺ cells, TNF-α, IL-1α/β, IL6, CCL2, CXCL5, COX-2, NOS2 ↑: CD3⁺ T cells	↓: Pro-inflammatory mediator	Reduction of recruitment of TAMs	Zhang et al. (2020b)
Dihydroartemisinin C₁₅H₂₄O₅	Artemisia caruifolia Buch.-Ham. ex Roxb	Terpenes	AOM/DSS mice (10 mg/kg)	–	↓: F4/80, CD68, IFN-β, IL-1β, IL-6, iNOS, MCP-1, TNF-α	–	Reduction of infiltration of TAMs	Bai et al. (2021)
Fucoxanthin C₄₂H₅₈O₆	Laminaria japonica Aresch	Carotenoids	AOM/DSS mice (30 mg/kg)	–	↓: CD206^high cells	–	Reduction of infiltration and recruitment of TAMs	Terasaki et al. (2019)
Panax notoginseng saponins C₄₇H₈₀O₁₇	Panax notoginseng (Burkill) F. H. Chen ex C. H. Chow	Saponin	AOM/DSS mice (75, 150 mg·kg⁻¹)	–	↓: STAT1 mediated IDO1 enzyme, IL-1β, Tregs	–	Reduction of recruitment of TAMs	Li et al. (2022c)
15-Hydroxy-6α,12-epoxy-7β,10αH,11βH-spiroax-4-ene-12-one (HESEO) C₁₅H₂₂O₃	Avicennia marina (Forsk.) Vierh	Terpenoids	CMT-93 mice (5 mg/kg)	–	↓: Number of CD11b⁺ cells and their subpopulations, macrophage populations	–	Reduction of infiltration and recruitment of TAMs	Zhao et al. (2020b)
1,2,3,4,6-Penta-O-galloyl-β-d-glucose C₄₁H₃₂O₂₆	Rhus chinensis Mill., Phyllanthus emblica L., Paeonia lactiflora Pall	Tannins	–	HCT116 cells (10–40 μM) and colon 26-M01 cells (50–200 μM)	–	↓: IL-2, IL-6, IL-10, IFN-γ, TNF-α	Reduction of infiltration and recruitment of TAMs	Yang et al. (2022)
Erianin C₁₈H₂₂O₅	Dendrobium nobile Lindl	Bibenzyls	–	SW480/HCT116 cells and THP1-derived macrophages (0–100 nM/24–96 h)	–	↓: CD47	Enhancement of phagocytosis of TAMs	Sun et al. (2020)
Chaetocin C₃₀H₂₈N₆O₆S₄	Chaetomium	Alkaloids	–	HCT116 cells and M-CSF-induced differentiated macrophages ( −)	–	↑: CD14-APC plus CFSE positive cells ↓: CD47	Enhancement of phagocytosis of TAMs	Wang et al. (2021c)
Berberine C₂₀H₁₈NO₄⁺	Coptis chinensis Franch	Alkaloids	Apc^Min/+ mice (1 mg/ml/d/28 days)	RAW 264.7 macrophage (25 μM/12h)	↓: IL-6, TNF-α, EGFR signalling	↓: IL-6, TNF-α	Regulation of pathways and cytokines	Li et al. (2017)
Lucidumol A C₃₀H₄₈O₄	Ganoderma lucidum (Curtis) P. Karst	Terpenoid	–	RAW 264.7 cells (0, 6.25, 12.5, 25 and 50 µM)	–	↓: TNF-α, IL-6, COX-2, iNOS	Regulation of pathways and cytokines	Shin et al. (2022)
Panaxynol C₁₇H₂₄O	Panax quinquefolius L	Fatty alcohols	AOM/DSS mice (2.5 mg/kg)	BMDMs (1 µM)	↓: CD68, Mrc1, MSR-1 genes, IL-1β, IL-6, IL-10, IL-13, TGF-β1	↓: M2 macrophages	Regulation of pathways and cytokines	McDonald et al. (2023)

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AOM/DSS azoxymethane/dextran sulfate sodium, TAMs tumour-associated macrophages, BMDM bone marrowderived macrophages, iNOS inducible nitric oxide synthase, Arg-1 arginase-1, TNF-α tumour necrosis factor-α, IL interleukin, MRC1 mannose receptor C-type 1, CCL2 CC-chemokine ligand 2, SPHK-S1P sphingosine kinase-sphingosine-1-phosphate, SOCS1 suppressor of cytokine signaling 1, IFN-γ interferon γ, MR mineralocorticoid receptor, Ym-1 chitinase 3-like 3, Fizz-1 found in inflammatory zone, JAK Janus Kinase, STAT signal transducer and activator of transcription, PI3K phosphatidylinositol 3-kinase, Akt protein kinase-B, MIF macrophage migration inhibitory factor, FOXP3 forkhead box P3 protein, NF-κB nuclear factor kappa-B, TGF-β transforming growth factor-β, VEGF vascular endothelial growth factor, HIF-1α hypoxia-inducible factor-1α, HK II hexokinase II, YAP1 yes-associated protein 1, PD-L1 programmed cell death-ligand 1, TEX tumour derived exosome, MCP-1 monocyte chemoattractant protein 1, COX-2 cyclooxygenase-2, PD-1 programmed death 1, IDO1 indoleamine 2,3-dioxygenase 1; Tregs regulatory T cells, MSR-1 mannose scavenger receptor 1

Regulation of polarization of TAMs

Natural compounds modulate TAMs in three main ways: inducing M1 macrophage polarization, inhibiting M2 macrophage polarization and promoting M2 macrophage repolarization to M1 macrophage, and these ways are mostly co-existing and interacting. We have plotted Fig. 3 to clarify the type and amount of natural compounds-targeted TAMs that are polarized to exert anti-CRC.

Fig. 3 — Graph of natural compounds exerting anti-CRC effects by regulating the polarization of TAMs, with 26 natural compounds. Figure represents 26 natural compounds that can act to inhibit CRC by modulating the polarization of TAMs. Six compounds (in red), represented by AS-IV, HESEO, etc., can polarize M2-type TAMs to M1-type TAMs to inhibit CRC. Eleven compounds (blue), represented by Quercetin, Piceatannol, etc., inhibit the polarization of M2-type TAMs to suppress CRC. Four compounds (brown), represented by Fucoidan, Dioscin, and others, can both inhibit the polarization of M2-type TAMs and promote the polarization of M1-type TAMs to inhibit CRC. Two compounds (pink), represented by PTPS-1–2 and Vitexin, promote the polarization of M1-type TAMs to inhibit CRC, whereas one compound (pink), berberine, inhibits the polarization of M1-type TAMs and inflammatory responses to inhibit CRC. The 2 compounds represented by GpS, PA/PO (green) can exert anti-inflammatory effects and modulate gut microbes to inhibit CRC by promoting M1 polarization to M2 type. M0, M0 macrophages; M1, M1 macrophages; M2, M2 macrophages; PTPS-1–2, An arabinogalactan; NF-κB, nuclear factor kappa-B; iNOS, inducible nitric oxide synthase; TNF-α, tumour necrosis factor-α; IL, interleukin; TGF-β, transforming growth factor-β; Arg-1, arginase-1; SPHK-S1P, sphingosine kinase-sphingosine-1-phosphate; JAK, Janus Kinase; STAT, signal transducer and activator of transcription; Ym-1, chitinase 3-like 3; Fizz-1, found in inflammatory zone; MCP-1, monocyte chemoattractant protein 1; VEGF, vascular endothelial growth factor; COX-2, cyclooxygenase-2; PD-1, programmed death 1; MIF, Macrophage migration inhibitory factor; HIF-1α, Hypoxia-inducible factor-1α; HK II, hexokinase II; YAP1, Yes-associated protein 1; Akt, protein kinase-B; OV, Ovatodiolide; NO, nitric oxide; MPS, 2-methylpyridine-1-ium-1-sulfonate; PD-L1, programmed cell death-ligand 1; TEX, Tumor derived exosome; IFN-γ, interferon γ; GpS, Gynostemma pentaphyllum saponins; CXCL, C-X-C chemokine ligand; FOXP3, forkhead box P3 protein; MR, mineralocorticoid receptor; PA, patchouli alcohol; PO, pogostone; AS-IV, Astragaloside IV; Mrc1, mannose receptor C-type 1; HESEO, 15-hydroxy-6α,12-epoxy-7β,10αH,11βH-spiroax-4-ene-12-one; GA, Gambogic acid; PI3K, phosphatidylinositol 3-kinase; CBD, Cannabidiol

In LPS- or IL-4-induced bone marrow-derived macrophages (BMDM) models and MDSCs, Dioscin promoted M1 macrophage polarization and inhibited M2 macrophage polarization, and inhibited azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced tumorigenesis early in the CAC mouse model (Xun et al. 2023).

Cuban brown propolis and its major component nemorosone affected the interaction between CRC HT-29 cells and TAMs by inhibiting the viability and modulating the polarization of M2-like macrophages and reducing EMT-related markers, thereby suppressing the proliferation, migration and invasion of CRC cells (Frion-Herrera et al. 2020).

Vitexin exerted antitumour effects by decreasing the number of M1-type macrophages in adjacent non-cancerous inflammatory tissues while upregulating M1 macrophage polarization in colon tumour tissues of CAC mice (Chen et al. 2021b).

Triptolide inhibited colon cancer both in vivo and in vitro by downregulating the expression of Arg-1, CD206, and IL-10 and delaying the polarization of TAMs towards an anti-tumour M2 phenotype, and Triptolide also suppressed the migration of colon cancer cells by decreasing VEGF expression (Jiang et al. 2021). Triptolide reversed the high expression of CD206, an important marker of M2 macrophages in the model group, and thus inhibited the activity of TAMs and M2 polarization in the microenvironment of colitis-associated colon cancer (CACC) model, specifically by the mechanism that Triptolide inhibited the sphingosine kinase-sphingosine-1-phosphate (SPHK-S1P) signalling pathway, and effectively reduced the expression of S1P and SPHK1/S1PR1/S1PR2 in macrophages, and clearly suppressed S1P-mediated activation of ERK protein phosphorylation (Li et al. 2020c). Furthermore, in THP-1 macrophages and AOM/DSS-induced ICR-1 colon tumour mice, Triptolide down-regulated the mRNA expression levels of Arg-1, CD206, CD204, and CD163, suggesting that Triptolide suppresses macrophage polarization towards the M2 phenotype (Li et al. 2020d).

Celastrol inhibited CRC cell growth by promoting macrophage polarization from M2 to M1 via the ERK/MAPK pathway and associated cytokines such as IL-32 and adhesion proteins such as CD155 (Wang et al. 2023d).

Quercetin inhibited autophagy of M2 TAMs and induced their differentiation into M1 TAMs, thereby significantly reversing the promotion of CRC cell proliferation by M2 TAMs (Chen et al. 2022).

miR-155-5p downregulates suppressor of cytokine signaling 1 (SOCS1) expression to suppress inflammatory responses and is a key target for regulating macrophage polarization. It was confirmed that berberine upregulated SOCS1 protein levels by inhibiting miR-155-5p expression, which in turn inhibited M1 phenotype macrophage polarization as well as IL-1β, IL-6 and TNF-α levels, suggesting that the inhibitory effect of berberine on CRC is dependent on its anti-inflammatory activity; however, in the AOM/DSS mouse model, the berberine inhibited M1 macrophage infiltration in both paraneoplastic non-cancerous and tumour tissues, and how to balance the polarization of the M1 phenotype still needs further investigation (Ling et al. 2023).

Patchouli Essential Oil (PEO) and its derivatives patchouli alcohol (PA) and pogostone (PO) polarised M1 macrophages to an M2 macrophage phenotype in an Apc^Min/+ mouse model, remodelled the inflammatory milieu of Apc^Min/+ mice and improved the gut microbiota to exert anti-CRC effects (Leong et al. 2022).

STAT3 signalling has been shown to upregulate CD206⁺ to enhance M2 macrophage polarization; Cucurbitacin B inhibited CRC cell proliferation and migration by reducing M2 macrophage polarization through downregulation of the JAK2/STAT3 signalling pathway on the one hand, and by inducing T-cells to infiltrate into the tumour and upregulating the expression of CD4 and CD8 in the TME on the other (Zhang et al. 2022).

Bigelovin enhanced anti-tumour immunity by decreasing IL-4 to inhibit M2 macrophage polarization while up-regulating IFN-γ to promote M1 macrophage polarization; in addition, Bigelovin inhibited tumour growth and liver/lung metastasis by down-regulating the IL6/STAT3 pathway in the CRC HCT116 and colon 26-M01 mouse models (Li et al. 2018b).

Cannabidiol (CBD) exerted its anti-CRC effect by inhibiting the PI3K-Akt signalling pathway and related downstream target genes, shifting the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis to promote the polarization of the M2 type to the M1 type; in addition, CBD enhanced the sensitivity of MC38 hormonal mice to anti-PD-1 immunotherapy because of its reprogramming effect on macrophages (Sun et al. 2023).

Macrophage migration inhibitory factor (MIF) promoted macrophage polarization in TME. Bufalin down-regulated the expression of MIF by targeting the SRC-3 protein in CRC chemoresistant cells, thereby inhibiting M2 macrophage polarization and reversing chemoresistance in CRC (Chen et al. 2021c).

Gynostemma pentaphyllum saponins (GpS) and Ganoderma lucidum polysaccharides (GLP) exerted anti-inflammatory effects by promoting the conversion of M1 TAMs into M2 TAMs to improve the inflamed intestinal barrier in Apc^Min/+ mice and modulate the gut microbiota (GM) to treat CRC (Khan et al. 2019).

Arabinogalactan (PTPS-1-2) inhibited the proliferation of RKO cells by activating the NF-κB signalling pathway to promote macrophage polarization to the M1 type (Xu et al. 2023).

Gambogic acid (GA) and GA liposomes inhibited CRC tumour progression by repolarising type 2 TAMs to type 1 TAMs, with reversal of M2-type macrophages to M1 and up-regulation of M1 markers (CD86) in CT26 tumour cells, and in tumour tissues of CT26-homozygous mice, intra-tumour M1 macrophages and IFNγ⁺ CD8⁺ T cells were increased and intra-tumour TGF-β⁺ CD206⁺ M2 macrophages were decreased (Wang et al. 2023e).

In U937 cells, β-Carotene (BC) inhibited M2 macrophage polarization by down-regulating the M2-associated markers Arg-1, TGF-β1 mRNA levels, CD163, and PPAR-g protein levels and thereby inhibiting M2 macrophage polarization, which may be associated with inhibition of the IL-6/STAT3 pathway; also in the AOM/DSS mouse model, BC suppressed mRNA levels of CD206, Arg-1 and chitinase 3-like 3 (Ym-1), and protein levels of CD163 and PPAR-g in colonic tissues, suggesting that BC inhibits infiltration and polarization of M2 TAMs (Lee et al. 2020).

In the mouse macrophage RAW 264.7 cell line, palmitic acid attenuated the expression of the M2 marker CD163 and the secretion of IL-10 and increased the expression of the M1 marker CD68 and the secretion of IL-12, suggesting that palmitic acid modulates the switch from a tumourigenic M2 to a pro-inflammatory M1 phenotype; also in mouse CRC (CT-26 and MC-38) cell lines, ceramide and palmitic acid inhibited M2 TAMs-promoted EMT and migration of CRC cells by a mechanism that may be the result of inhibition of IL-10, SNAI1, and vimentin expression and the up-regulation of E-cadherin and thus IL-10-STAT3- NF-κB signalling axis (Araujo et al. 2020).

Piceatannol exerted anti-CRC lung metastasis by limiting the polarization of M2-like macrophages in TME, blocking the TGF-β1 positive feedback autocrine/paracrine circuit, and attenuating the expression of CD163 (Chiou et al. 2022).

Mannose suppressed the progression of CAC in mice by promoting the normalisation of TAMs polarization, as evidenced by a decrease in the expression of the TAMs marker proteins VEGF, Arg-1, and HIF-1α and significant inhibition of the M2-like phenotypic polarization of TAMs (Liu et al. 2022).

Ovatodiolide (OV) significantly reduced the expression of the M2 macrophage markers Arg-1 and CD23 and inhibited the levels of Yes-associated protein 1 (YAP1), NF-κB, Akt, and IL-6, and OV also reduced the IL -6-induced CD133⁺ cells in the HCT116 and DLD-1 cell lines numbers and inhibited colonic ball formation, and overall OV inhibited M2 TAMs polarization through the mechanism of action of silencing YAP1 (Huang et al. 2017).

2-Methylpyridine-1-ium-1-sulfonate (MPS) significantly up-regulated the expression of CD80 (M1 marker) on the surface of THP-1 macrophages and decreased the expression of PD-L1 and TGF-β, TNF-α; meanwhile, MPS treatment of HT-29 cells attenuated the Tumour derived exosome (TEX)-induced high expression of CD163, PD-L1, and IL-10 in THP- 1 macrophage, indicating that MPS promoted the conversion of THP-1 macrophages to the M1 phenotype and attenuated TEX-mediated M2-like polarization; MPS also directly induced apoptosis and cell cycle arrest in HT-29 cells and reduced cell migration capacity (Rastegari-Pouyani et al. 2022).

In the M2 macrophage and CT26 mouse models, treatment with Astragaloside IV (AS-IV) resulted in decreased expression of Arg-1 and Mrc-1, increased levels of IL-12 and NOS2 in M2 macrophages, decreased percentage of CD11b⁺F4/80⁺CD206^hi M2 macrophages, and CD11b⁺F4/80⁺ MHCII^hi M1 macrophage percentage increased, anti-inflammatory factors TGF-β, IL-10, and VEGFA levels decreased, and pro-inflammatory factors IFN-γ, IL-12, and TNF-α levels increased in the tumour tissue, which confirmed that AS-IV induced the polarization of M2-type macrophages to M1-type (Liu et al. 2020b).

In a mouse model of colon cancer xenografts, fucoidan enhanced macrophage glycolysis, downregulated CD206, and upregulated CD68 expression through activation of the TLR4-mediated PI3K/AKT/mTOR signalling axis, suggesting that fucoidan increased M1 macrophage infiltration and promoted macrophage polarization towards the M1 phenotype and its mediated apoptosis (Deng et al. 2022).

15-Hydroxy-6α,12-epoxy-7β,10αH,11βH-spiroax-4-ene-12-one (HESEO) up-regulated IFN-γ, the T-cell recruitment factor CXCL9, and the inflammatory factors TNF-α and IL-15, while decreasing the M2 alternative activation markers Ym-1 and Arg-1, indicating that HESEO repolarised M2 macrophages to an M1 phenotype that could improve anti-tumour T cell responses (Zhao et al. 2020b).

4,4′-Dihydroxystilbene prevented colon tumour growth in AOM/DSS mice by inhibiting TAMs-induced cytokine (IL-1β and IL-6) and chemokine (MCP-1) expression levels, suppressing colonic VEGF and PD-1 levels, while in M2 polarised THP-1 macrophages it significantly reduced PD-1 levels to inhibit M2 macrophage differentiation and activation (Kimura et al. 2020).

Macelignan prevented IL-1β/NF-κB-dependent CRC metastasis by inhibiting the PI3K/AKT signaling pathway and thereby inhibiting the M2 polarization of TAMs; moreover, in vivo experiments demonstrated that Macelignan inhibited M2 macrophage-mediated CRC cell metastasis (Che et al. 2024).

The above results proved that natural compounds can exert anti-CRC effects by regulating the polarization of TAMs, mostly by inhibiting M2 polarization and promoting M1 polarization, with clear efficacy. However, several natural compounds still exert anti-CRC effects through M1 to M2 polarization, so the relationship between M1 and M2 polarization and the mechanism of anti-cancer effects need to be further explored. We found that most of the natural compounds were subjected to both in vivo and in vitro experiments, but there are still some natural compounds that were subjected to only one of these experiments, which undoubtedly is not conducive to the full elaboration of the roles of these natural compounds in inducing the polarization of TAMs. Triptolide is the more studied natural compound and down-regulation of the M2 macrophage marker CD206 was observed in all 3 experiments, which could be a future research direction with potential.

Reduction of infiltration and recruitment of TAMs

Infiltration and recruitment of TAMs can promote tumour development, and since most TAMs are dominated by M2 macrophages, inhibition of infiltration and recruitment of TAMs can exert anti-tumour effects at the upstream stage.

Triptolide inhibited CRC proliferation by modulating the NF-κB and ERK 1/2 axes to downregulate the expression of the chemokine CXCL12 to reduce the infiltration of TAMs (Jiang et al. 2021).

In the AOM/DSS mice model, Triptolide inhibited the massive recruitment of macrophages in tumours (Li et al. 2020c). Furthermore, in AOM/DSS-induced ICR-1 colon tumour mice, Triptolide down-regulated the mRNA expression levels of CD68 and MCP-1, suggesting that Triptolide may inhibit the infiltration of TAMs into the intestinal tumour stroma of mice by blocking the MCP-1 pathway (Li et al. 2020d).

Dihydroisotanshinone I (DT) blocked the ability of colon cancer cells to recruit macrophages by decreasing the secretion of CCL2 in macrophages, and 5 μM DT inhibited the proliferation of CRC cells even better than the same concentration of OXA (Lin et al. 2017).

Emodin treatment of AOM/DSS mice decreased the abundance of CD206⁺ M2-like macrophages in the lamina propria of the colon, decreased the ratio of M2/M1 macrophages in the colon, and increased the number of M1 macrophages, but there were no significant changes in the M1- and M2-related factors; at the same time, there was a significant increase in the expression of NOS2 (a marker of M1 and tumour killing), and the mechanism may be that Emodin decreases the expression of P2X7 and STAT3 signalling in the bone tissue of AOM/DSS mice (Sougiannis et al. 2022). In addition, Emodin reduced the recruitment of inflammatory cells (CD11b⁺ and F4/80⁺) and inhibited the expression of cytokines (TNF-α, IL1-α/β, IL-6, CCL2, CXCL5) and pro-inflammatory enzymes (COX-2, NOS2) in the TME of the AOM/DSS model, suggesting that Emodin exerts its anti-CRC; in vitro experiments, Emodin inhibited the release of pro-inflammatory mediators from LPS-stimulated RAW 264.7 macrophages and hindered CRC progression (Zhang et al. 2020b).

In a mice model of CAC stimulated with AOM and DSS, Dihydroartemisinin significantly down-regulated the expression of F4/80 and CD68 and reversed macrophage infiltration in the colonic mucosa, while decreasing the expression of pro-inflammatory cytokines IFN-β, IL-1β, IL-6, iNOS, MCP-1, and TNF-α mRNA, as well as the expression of IL-6 and TNF-α proteins, which resulted in the inhibition of the development of CAC (Bai et al. 2021).

In AOM/DSS mice, 30 mg/kg Fucoxanthin treatment significantly reduced the number of CRC TAMs-like CD206^high cells (Terasaki et al. 2019).

Panax notoginseng saponins alleviated the immunosuppression of Treg cells in the CAC microenvironment and remodelled the immune microenvironment of CAC by inhibiting STAT1-directly mediated expression of indoleamine 2,3-dioxygenase 1 (IDO1), decreasing macrophage aggregation in the peritoneal exudate, down-regulating the level of IL-1β in the colonic tissues and decreasing the differentiation of Treg cells (Li et al. 2022c).

HESEO decreased the percentage of total tumour-infiltrating CD11b⁺ cells and their subpopulations (macrophages, granulocytes, monocytes) while increasing the percentage of B-cells and NK-cells and significantly decreasing the number of macrophage populations, suggesting that HESEO prevents macrophage recruitment in tumour tissue (Zhao et al. 2020b).

Increased TAMs and MDSCs in mice CRC cells elevated the odds of liver metastasis, and 1,2,3,4,6-Penta-O-galloyl-β-D-glucose increased the number of T cells as well as the levels of IL-2 and IFN-γ and decreased the number of macrophages and MDSCs as well as the expression of IL-6, IL-10, and TNF-α, which inhibited the proliferation and migration of HCT116 and colonic 26-M01 cells (Yang et al. 2022).

From the above, it is clear that natural compounds can inhibit CRC progression by inhibiting the infiltration and recruitment of TAMs. However, most of the natural compounds have only been tested in vivo but not in vitro, which makes the results of these experiments unable to circumvent the individual differences of experimental models and the errors caused by environmental factors, so the corresponding in vitro experiments should be carried out on natural compounds such as Triptolide, Dihydroartemisinin and Fucoxanthin. At the same time, 2 experiments were conducted on Emodin, one of which showed that NOS2 was elevated; interestingly, the other showed that NOS2 was decreased. Whether this situation is caused by the different doses of Emodin or something else is also a point of concern for us in the future.

Enhancement of phagocytosis of macrophages

Macrophages have a strong phagocytic ability and can phagocytose bacteria, viruses, foreign cells, damaged cells, tumour cells and other harmful substances. At the same time, M1 macrophages can phagocytose tumour cells, inhibiting tumour growth and recurrence.

CD47 protein regulated macrophage phagocytosis by mediating “self/do-not-eat-me” signalling and was often highly expressed in tumour cells to promote immune escape; Erianin inhibited CD47 expression by decreasing the enrichment of the H3K27 acetyl tag in the promoter region of CD47, thereby enhancing macrophage phagocytosis to inhibit the growth of CRC (Sun et al. 2020).

Chaetocin induced apoptosis in CRC cells independent of 5-FU sensitivity and enhanced phagocytosis in macrophages by causing ROS accumulation and activation of c-Jun N-terminal kinase (JNK)/c-Jun, suggesting that Chaetocin could be a candidate for CRC chemotherapy (Wang et al. 2021c).

It can be seen that macrophages have a solid ability to phagocytose tumour cells, but the phagocytosis of M1 macrophages has been less studied and may be a key direction for future research. The next step could also be to perform the corresponding in vivo experiments on Erianin and Chaetocin to better confirm their role in enhancing macrophage phagocytosis to exert anti-CRC. We detected a decrease in CD47 in both experiments, so it is a promising line of research to see how CD47 can be regulated to better play a role in phagocytosis of tumours by macrophages.

Regulation of signalling pathways and cytokines

The development of CRC is affected by a variety of signalling pathways and cytokines, and the modulation of signalling pathways and related pro- or anti-cancer cytokines has become one of the critical ways to fight CRC.

Berberine reduced the expression of pro-inflammatory cytokines IL-6 and TNF-α released by macrophages in the chronic inflammatory microenvironment of Apc^Min/+ mice and down-regulated EGFR signalling to inhibit CRC cell proliferation (Li et al. 2017).

In RAW 264.7 cells, Lucidumol A could regulate tumour progression by controlling the inflammatory response of macrophages in the tumour microenvironment, such as inhibition of TNF-α, IL-6, COX-2 and iNOS, while Lucidumol A inhibited the proliferative and migratory capacity of HCT116 cells and increased cell death (Shin et al. 2022).

In AOM/DSS mice, panaxynol reduced the relative abundance of colonic macrophages in the lamina propria, suppressed the expression of the pan-macrophage-associated genes CD68, Mrc-1 and mannose scavenger receptor 1 (MSR-1), and down-regulated the expression of the pro-inflammatory genes IL-1β, IL-6, and pro-neoplastic genes IL-10, IL-13, and TGF-β1; these results suggest that panaxynol works by inhibiting macrophages and modulating the colon inflammatory milieu to treat CRC (McDonald et al. 2023).

Through the above compounds to regulate the signalling pathway and cytokine pathway, it was found that all three natural compounds down-regulated the expression of IL-6 and IL-6 might be a potential therapeutic target. Meanwhile, anti-inflammatory can treat CRC, but M2 macrophage can anti-inflammatory but promote CRC, so anti-inflammatory and M2 macrophage regulation of the mechanism of action of CRC needs to be specifically further study, which also further suggests that the mechanism of the polarization of M1 and M2 macrophages in the anticancer has a multifaceted nature and is not purely M2-type cancer-promoting and M1-type anticancer is so simple, but also associated with a variety of cytokines, such as inflammatory factors or oncogenes, which need to be further explored.

Prospects for novel natural compounds-based drugs against CRC

Although natural compounds have good anti-CRC effects, there are several problems that need urgent attention, including their difficulty in dissolving in water, poor solubility, limited absorption by the human body, and intolerance to high temperatures. It has been noted that curcumin has a vastly increased anti-CRC potential when prepared as stable nanocrystals in vitro, with IC₅₀ values of nanocrystals ranging from 20 to 70 µg/mL (70–190 µM) on the HT-29 cell line, a result that exceeds the in vitro performance of many of the chemotherapeutic agents in current use (Lizonova et al. 2022). In the future, novel biologics derived from natural compounds, including nano-formulations and synthetic compounds, have the potential to exhibit improved anti-CRC effects by specifically targeting TAMs. These approaches represent a promising new direction for the development of innovative drugs in the field.

Nanoparticle formulations

Nanoformulation refers to a category of advanced pharmaceutical preparations that utilise nanocarrier technology. These preparations are characterised by their ultrafine powder structure, which facilitates the penetration of drugs into the interstitial space of tissues, leading to improved bioavailability. Additionally, nanoformulations offer benefits such as stable and controlled drug release, enhanced drug targeting, and improved drug stability (Yazdimamaghani et al. 2025; Lu et al. 2024). Ursolic acid (UA) induced immunogenic cell death (ICD), whereas lentinan (LNT) promoted the polarization of the M2 phenotype to the M1 phenotype; the nanomedicine LNT-UA, which was self-assembled from UA and LNT, effectively remodelled the immunosuppressive TME and restored the immune system’s function, thus inhibiting CT26 CRC tumour model progression (Mao et al. 2022). A study developed a poly (D,L-lactide-co-glycolide) (PLGA)-based biomimetic nanoparticle, synthesised Hydroxymethyl phenylboronic acid conjugated PLGA (HPA), and subsequently wrapped a novel surface modification method to prepare a mannose-modified erythrocyte membrane (Man-EM) wrapped around HPA cores loaded with artesunate (AS) and chloroquine (CQ) to receive the biomimetic nanoparticle HPA/AS/CQ.

Man-EM, which up-regulated ROS levels and down-regulated VEGF protein levels inhibited tumour cell proliferation and angiogenesis while repolarising M2 TAMs to M1 TAMs inhibited CRC (Peng et al. 2023). Peritoneal dissemination of colon cancer could be prevented by intraperitoneal administration of tocopheryl succinate nanoparticles, which have a longer intraperitoneal retention time and a wider biodistribution than intravenous injections and whose anticancer effects are attributed to the inhibition of cancer cell proliferation and the improvement of the intra-abdominal microenvironment such as the reduction of VEGFA, IL-10 levels and M2 TAMs (Hama et al. 2022). These suggest that nanoparticle formulations can enhance anti-CRC effectiveness by improving the utilisation of natural compounds and are a popular direction for future research.

Synthetic preparations

By employing synthetic modifications, researchers can overcome limitations associated with natural compounds. Synthetic preparations based on natural compounds are mostly new drug preparations manufactured by knocking out or changing certain unstable structures of drugs, which have advantages such as high solubility, stable efficacy and efficient utilisation and have been widely utilised and developed. 7S,15R-dihydroxy-16S,17S-epoxy-docosapentaenoic acid (diHEP-DPA) is a novel lysostaphin, synthesised from the substrate docosahexaenoic acid (DHA), that overcomes 5-FU chemo-resistance by reducing CSCs, inhibiting the infiltration of TAMs, and inhibiting the progression of EMT (Su et al. 2023). In addition, diHEP-DPA could exert anti-CRC effects by modulating the polarization of TAMs (inhibiting polarization from M0 macrophages to TAMs), blocking the CD47/SIRPα axis and thus enhancing phagocytosis of TAMs, inhibiting immunosuppression, inhibiting the EMT process, and tumour stemness by the specific mechanism that diHEP-DPA reduces the expression of markers of TAMs through inhibiting the NF-κB signalling pathway, and inhibits CRC via the ROS/STAT3 signalling pathway (Wang et al. 2021d). Inhibiting the polarization or survival of TAMs by blocking CSF-1/CSF-1R signalling has become a promising strategy for cancer immunotherapy, and compound 21 in the synthesized (Z)-1-(3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)-3-(isoxazol3-yl)urea derivatives possessed a good CSF-1R inhibitory activity (IC₅₀ = 2.1 nM), which enhanced anti-tumour immunity by inhibiting macrophage migration, reprogramming M2-like macrophages to an M1 phenotype, and which in turn inhibited CRC progression (Lv et al. 2021). Synthetic preparations play a crucial role in compensating for the limitations of natural compounds, enhancing their effectiveness and stability. However, it is worth noting that synthetic preparations often come with higher prices and production costs. Therefore, further exploration and optimisation of their production processes are necessary to make them more affordable and accessible. And Efforts in researching and refining the production methods of synthetic preparations are an important aspect of clinical drug development.

Problems and prospects

CRC ranks as the third most widespread type of cancer globally and is associated with a significant mortality rate. However, the exact causes and mechanisms underlying its development remain unclear, thus hindering the optimal effectiveness of treatment for CRC. Traditional approaches to treat CRC, including surgery, radiotherapy, targeted therapy, and immunotherapy, have shown promising results in terms of extending patient survival. Nonetheless, challenges such as drug resistance, unwanted reactions, and toxic side effects continue to be prevalent during treatment. Hence, there is a pressing necessity to discover alternative drugs that can effectively address these challenges. Natural compounds have emerged as vital therapeutic agents for CRC, thanks to their advantageous attributes of multitargeting, multipathway action, and high safety profile. TAMs are a significant element of the TME, exerting a critical influence on tumour development, progression, and metastasis. Within the TME, macrophages are recruited and transformed into TAMs, which continuously infiltrate and polarize. M1 macrophages assume a pro-inflammatory and anti-tumour function, while M2 macrophages adopt an anti-inflammatory and pro-tumour role. Notably, TAMs are predominantly composed of M2 macrophages, leading to the promotion of tumour progression. This paper presents a comprehensive review of the mechanisms through which TAMs have contributed to CRC over the past 5 years. Our analysis reveals that TAMs play a pivotal role in promoting CRC pathogenesis, proliferation, invasion, metastasis, angiogenesis, immune evasion, and tumour resistance and impact the prognosis of CRC patients.

Additionally, we explored the mechanisms by which natural compounds target TAMs to exert anti-CRC effects during the same period. Our findings demonstrate that these natural compounds primarily regulate TAM polarization, inhibiting M2 polarization while promoting M1 polarization. Furthermore, they reduce the infiltration and recruitment of TAMs, enhance macrophage phagocytosis, and modulate signalling pathways and cytokines associated with TAM activity. This targeted approach demonstrates precise efficacy in combating CRC by harnessing the influence of TAMs. Among the mechanisms employed to target TAMs, macrophage polarization, recruitment, and infiltration have garnered considerable attention. Natural compounds that act on these mechanisms have been the subject of more frequent and mature studies. The mechanism underlying the polarization of M1 and M2 macrophages in anti-cancer activities is intricate and multifaceted. It is not solely defined by a simplistic classification of M2 as cancer-promoting and M1 as anti-cancer. Instead, it also involves the interplay of inflammatory cytokines and oncogenes, which necessitates further exploration and investigation to fully comprehend their implications in cancer development and treatment. Indeed, other mechanisms, such as phagocytosis, cytokines, and signalling pathways, have received less attention and warrant further investigation in future studies. The specific mechanisms of action exhibited by natural compounds are diverse and offer promising avenues for research. Within the scope of this paper, Triptolide emerged as the most frequently studied natural compound. Triptolide demonstrates potential in exerting anti-CRC effects by regulating TAM polarization (inhibiting M2 polarization and promoting M1 polarization) and reducing TAMs infiltration and recruitment, among other mechanisms. Notably, the mechanism of action of Triptolide varies across different models, highlighting its complexity and the need for further research. Considering its potential, Triptolide may serve as a key drug in future investigations, aiding in the clarification of its precise mechanism of action in targeting TAMs for CRC treatment. This drug holds significant promise for future research endeavours, enabling a deeper understanding of how it can effectively target TAMs in the context of CRC therapy.

However, natural compounds also encounter certain limitations, such as poor solubility (or insolubility in water), which can affect their therapeutic efficacy. In many cases, a larger dosage is required to achieve the desired therapeutic effects. To overcome these challenges, enhancing the inhibitory effect of natural compounds on CRC can be achieved through strategies like nanoparticle drug delivery and synthetic preparations. These approaches have the potential to enhance the efficacy and bioavailability of natural compounds in the treatment of CRC. Indeed, there is a notable scarcity of safety, pharmacokinetic, and pharmacodynamic studies pertaining to natural compounds. To fully develop these novel drugs and ascertain their effectiveness, future clinical trials are imperative.

Chemical compounds

Dioscin (PubChem CID:119245).
Nemorosone (PubChem CID:637105).
Vitexin (PubChem CID:5280441).
Triptolide (PubChem CID:107985).
Celastrol (PubChem CID:122724).
Quercetin (PubChem CID:5280343).
Berberine (PubChem CID:2353).
Patchouli alcohol (PubChem CID:10955174).
Pogostone (PubChem CID:54695756).
Cucurbitacin B (PubChem CID:5281316).
Bigelovin (PubChem CID:3080597).
Cannabidiol (PubChem CID:644019).
Bufalin (PubChem CID:9547215).
Gynostemma pentaphyllum (PubChem CID:46887681).
Arabinogalactan (PubChem CID:24847856).
Gambogic Acid (PubChem CID:9852185).
β-Carotene (PubChem CID:5280489).
Palmitic acid (PubChem CID:985).
Piceatannol (PubChem CID:667639).
Mannose (PubChem CID:18950).
Ovatodiolide (PubChem CID:38347030).
2-methylpyridine-1-ium-1-sulfonate (PubChem CID:140652969).
Astragaloside IV (PubChem CID:13943297).
Fucoidan (PubChem CID:129532628).
15-hydroxy-6α,12-epoxy-7β,10αH,11βH-spiroax-4-ene-12-one (PubChem CID:139585021).
4,4′-dihydroxystilbene (PubChem CID: 9548839).
Macelignan (PubChem CID:10404245).
Dihydroisotanshinone I (PubChem CID:89406).
Emodin (PubChem CID:3220).
Dihydroartemisinin (PubChem CID:3000518).
Fucoxanthin (PubChem CID:5281239).
Panax notoginseng saponins (PubChem CID: 90657714).
1,2,3,4,6-Penta-O-galloyl-β-D-glucose (PubChem CID: 65238).
Erianin (PubChem CID:356759).
Chaetocin (PubChem CID:11657687).
Lucidumol A (PubChem CID:475410).
Panaxynol (PubChem CID:5469789).

Acknowledgements

We thank Figdraw (www.figdraw.com) for helping create the figures.

Abbreviations

CRC: Colorectal cancer
TME: Tumour microenvironment
TAMs: Tumour-associated macrophages
JAK: Janus Kinase
STAT: Signal transducer and activator of transcription
PI3K/Akt: Phosphatidylinositol 3-kinase/protein kinase-B
IL: Interleukin
SILS: Single incision laparoscopic surgery
EGFR: Epidermal growth factor receptor
VEGF: Vascular endothelial growth factor
OS: Overall survival
HER2: Human epidermal growth factor receptor 2
PD-1/PD-L1: Programmed death 1/programmed cell death-ligand 1
JNK: C-Jun N-terminal kinase
MACC1: Metastasis-associated in colon cancer 1
NF-κB: Nuclear factor kappa-B
MAPK: Mitogen-activated protein kinase
ECM: Extracellular matrix
MDSCs: Myeloid-derived suppressor cells
ICIs: Immune checkpoint inhibitors
IFN-γ: Interferon γ
CCL2: CC-chemokine ligand 2
CXCL: C-X-C chemokine ligand
Th1: T helper cell type 1
TNF-α: Tumour necrosis factor-α
LPS: Lipopolysaccharide
TLR: Toll-like receptors
iNOS: Inducible nitric oxide synthase
COX-2: Cyclooxygenase-2
IL-10R: IL-10 receptor
Arg-1: Arginase-1
TGF-β: Transforming growth factor-β
EMT: Epithelial-mesenchymal transition
MMPs: Matrix metalloproteinases
ROS: Reactive oxygen species
GLUL: Glutamate-ammonia ligase
OXA: Oxaliplatin
m⁶A: N⁶-Methyladenosine
PGE2: Prostaglandin E 2
GDNPs: Ginseng-derived nanoparticles
MyD88: Myeloid differentiation antigen 88
CKI: Compound kushen injection
HCC: Hepatocellular carcinoma
CAC: Colitis-associated carcinogenesis
Act1: NF-κB activator 1
Apc: Adenomatous polyposis coli
MCP-1: Monocyte chemoattractant protein 1
CCR2: CC chemokine receptor 2
PDGF: Platelet-derived growth factor
ERK: Extracellular signal-regulated protein kinase
SAA1: Serum amyloid A1
NRP1: Neuropilin 1
CTSK: Cathepsin K
mTOR: Mammalian target of rapamycin
HIF-1α: Hypoxia-inducible factor-1α
TRIB3: Tribbles Pseudokinase 3
MRC1: Mannose receptor C-type 1
Tregs: Regulatory T cells
DPD: Dihydropyrimidine dehydrogenase
5-FU: 5-Fluorouracil
CSCs: Cancer stem cells
DFS: Disease-free survival
TF: Disease-free survival
ANM: Adjacent normal mucosa
DSS: Disease-specific survival
ADGRE1: Adhesion G protein-coupled receptor family
EMR1-TC: EMR1 in tumour cells
PPEP: A polyphenol-rich extract isolated from Pleurotus eryngii
BMDM: Bone marrow derived macrophages
AOM/DSS: Azoxymethane/dextran sulfate sodium
CACC: Colitis-associated colon cancer
SPHK-S1P: Sphingosine kinase-sphingosine-1-phosphate
SOCS1: Suppressor of cytokine signaling 1
PEO: Patchouli Essential Oil
PA: Patchouli alcohol
PO: Pogostone
CuB: Cucurbitacin B
CBD: Cannabidiol
MIF: Macrophage migration inhibitory factor
GpS: Gynostemma pentaphyllum saponins
GLP: Ganoderma lucidum polysaccharides
GM: Gut microbiota
PTPS-1-2: An arabinogalactan
GA: Gambogic acid
BC: β-Carotene
HESEO: 15-Hydroxy-6α,12-epoxy-7β,10αH,11βH-spiroax-4-ene-12-one
PA: Palmitic acid
Cer: Ceramide
PIC: Picetanol
OV: Ovatodiolide
YAP1: Yes-associated protein 1
TEX: Tumour derived exosome
AS-IV: Astragaloside IV
DT: Dihydroisotanshinone I
PGG: 1,2,3,4,6-Penta-O-galloyl-β-D-glucose
PNS: Panax notoginseng saponins
IDO1: Indoleamine 2,3-dioxygenase 1
DHA: Dihydroartemisinin
Fx: Fucoxanthin
MSR-1: Mannose scavenger receptor 1
AS: Artesunate
CQ: Chloroquine
UA: Ursolic acid
ICD: Immunogenic cell death
LNT: Lentinan
HPA: Hydroxymethyl phenylboronic acid conjugated PLGA
Man-EM: Mannose-modified erythrocyte membrane
diHEP-DPA: 7S,15R-dihydroxy-16S,17S-epoxy-docosapentaenoic acid
Ym-1: Chitinase 3-like 3
Fizz-1: Found in inflammatory zone

Author contributions

Conceptualization: Wen-Ting Li, Wen-Li Qiu, Hong-Guang Zhou; Methodology: Wen-Ting Li, Wen-Li Qiu, Hong-Guang Zhou; Formal analysis and investigation: Wei-Chen Yuan, Jie-Xiang Zhang, Hai-Bin Chen, Yu-Pei Zhuang, Hong-Li Zhou; Writing—original draft preparation: Wei-Chen Yuan, Jie-Xiang Zhang, Hai-Bin Chen; Writing—review and editing: Wei-Chen Yuan, Jie-Xiang Zhang, Yu-Pei Zhuang, Hong-Li Zhou, Wen-Ting Li, Wen-Li Qiu, Hong-Guang Zhou; Supervision: Wen-Ting Li, Wen-Li Qiu, Hong-Guang Zhou. All authors have read and approved the submitted version.

Funding

This work was supported by the National Natural Science Foundation of China (81973737, 82001883, and 81804058), the Key Project of Jiangsu Province Traditional Chinese Medicine Science and Technology Development Project (ZD202301), the second session of the National Famous Chinese Medicine Workshop Construction Project (National Traditional Chinese Medicine Human Education Letter [2022] No. 245), Wu Mianhua National Famous Elderly Chinese Medicine Experts Inheritance Workshop Construction Project (National Traditional Chinese Medicine Human Education Letter [2022] No. 75) and Wu Mianhua Jiangsu Province, Famous Elderly Chinese Medicine Experts Inheritance Workshop Construction Project (Su Chinese Medicine Science and Education [2021] No. 7).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Footnotes

The original online version of this article was revised due to Incomplete/Incorrect funding note. Now, it has been corrected to: Funding This work was supported by the National Natural Science Foundation of China (81973737, 82001883, and 81804058), the Key Project of Jiangsu Province Traditional Chinese Medicine Science and Technology Development Project (ZD202301), the second session of the National Famous Chinese Medicine Workshop Construction Project (National Traditional Chinese Medicine Human Education Letter [2022] No. 245), Wu Mianhua National Famous Elderly Chinese Medicine Experts Inheritance Workshop Construction Project (National Traditional Chinese Medicine Human Education Letter [2022] No. 75) and Wu Mianhua Jiangsu Province, Famous Elderly Chinese Medicine Experts Inheritance Workshop Construction Project (Su Chinese Medicine Science and Education [2021] No. 7).

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Weichen Yuan, Jiexiang Zhang and Haibin Chen have contributed equally to this work as co-first authors.

Wenting Li, Wenli Qiu and Hongguang Zhou have contributed equally to this work as co-corresponding authors.

Change history

12/28/2024

The original online version of this article was revised due to Incomplete/Incorrect funding note. Now, it has been corrected.

Change history

12/28/2024

A Correction to this paper has been published: 10.1007/s00432-024-06067-9

Contributor Information

Wenting Li, Email: 260729@njucm.edu.cn.

Wenli Qiu, Email: fsyy00698@njucm.edu.cn.

Hongguang Zhou, Email: 260105@njucm.edu.cn.

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Associated Data

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Data Availability Statement

No datasets were generated or analysed during the current study.

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PERMALINK

Natural compounds modulate the mechanism of action of tumour-associated macrophages against colorectal cancer: a review

Weichen Yuan

Jiexiang Zhang

Haibin Chen

Yupei Zhuang

Hongli Zhou

Wenting Li

Wenli Qiu

Hongguang Zhou

Abstract

Introduction

TAMs and TME

Fig. 1.

TAMs contribute to CRC

TAMs modulate CRC pathogenesis

TAMs promote CRC proliferation

TAMs promote CRC invasion and metastasis

TAMs promote CRC angiogenesis

TAMs promote immune escape from CRC

TAMs promote treatment resistance in CRC

TAMs mediate prognosis in CRC

Treatment of TAMs and CRC

Mechanisms of natural compounds targeting TAMs for CRC treatment

Fig. 2.

Table 1.

Regulation of polarization of TAMs

Fig. 3.

Reduction of infiltration and recruitment of TAMs

Enhancement of phagocytosis of macrophages

Regulation of signalling pathways and cytokines

Prospects for novel natural compounds-based drugs against CRC

Nanoparticle formulations

Synthetic preparations

Problems and prospects

Chemical compounds

Acknowledgements

Abbreviations

Author contributions

Funding

Data availability

Declarations

Conflict of interest

Footnotes

Contributor Information

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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