Progress of traditional Chinese medicine in the prevention and treatment of colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, ranking among the highest in both incidence and mortality rates. Traditional Chinese medicine, with a history spanning thousands of years, has demonstrated unique efficacy and advantages in the prevention and treatment of CRC, playing a pivotal role at all levels of China’s healthcare system. This article provides a comprehensive analysis and summary of traditional Chinese medicine’s contributions to CRC prevention, antitumor therapy, palliative care for advanced tumors, perioperative rehabilitation, and postoperative functional recovery.

Key Words: Colorectal cancer; Traditional Chinese medicine; Acupuncture; Prescriptions; Anti-tumor mechanism

Core Tip: Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, ranking high in both incidence and mortality rates. With a history spanning thousands of years, traditional Chinese medicine has shown unique efficacy and advantages in CRC prevention and treatment, playing a crucial role across all levels of China’s healthcare system. This article offers a comprehensive analysis and summary of traditional Chinese medicine’s contributions to CRC prevention, antitumor therapy, palliative care for advanced tumors, perioperative rehabilitation, and postoperative functional recovery.

INTRODUCTION

Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, with the highest incidence and mortality rates[1]. With a history spanning millennia, traditional Chinese medicine (TCM) has consistently played a crucial role in China’s medical systems at all levels. An increasing body of research demonstrates that various TCM components can intervene and inhibit CRC proliferation and invasion through multiple mechanisms, offering unique efficacy and advantages in CRC prevention and treatment[2,3].

The therapeutic measures of TCM encompass internal treatments such as compound herbal formulas, single herbs, herbal extracts, and patented Chinese medicines, as well as external therapies like acupuncture, massage, and qigong. Clinical studies have confirmed the efficacy of TCM in increasing survival time and improving the quality of life for CRC patients[4], while also demonstrating high safety profiles[5]. In recent years, natural plant- and mineral-based TCMs, including their extracts, multi-herb compounds and patented formulations[6], have demonstrated potent anti-tumor effects. When combined with modern treatments such as radiotherapy, chemotherapy, targeted therapy, and immunotherapy, these TCM interventions have synergistic and attenuating effects[7], garnering significant attention for TCM as alternative or complementary treatments for CRC. However, the complexity of TCM components and its unique theoretical framework, which emphasizes individualized treatment based on syndrome differentiation, pose significant challenges to high-quality clinical research and drug development. The difficulty in generating robust evidence largely continues to hinder the objective and standardized advancement of TCM.

With the ongoing and increasingly integrated application of TCM and modern medical treatments, numerous meaningful therapeutic collaborations have been implemented and validated, yielding positive outcomes. Consequently, an integrated system of TCM and Western medicine with distinct Chinese characteristics has emerged, becoming one of the primary medical models in China[8]. This article aims to systematically review and analyze the application of TCM in preventing high-risk factors for cancer development, anti-tumor treatment, palliative and maintenance therapy for advanced tumors, perioperative enhanced recovery, and postoperative functional rehabilitation. The goal is to provide a comprehensive reference for understanding the role of TCM in these areas (Figure 1).

Figure 1 The role of traditional Chinese medicine in the prevention and treatment of colorectal cancer. TCM: Traditional Chinese medicine; XLJDD: Xianlian Jiedu decoction; PZH: Pien Tze Huang; KJT: Ku-jin tea; YYFZBJS: Yi-Yi-Fu-Zi-Bai-Jiang-San; TXD: TiaochangXiaoliu decoction; LJZD: Liujunzi decoction; DCQ: Dachengqi decoction; DZP: Dahuang Zhechong Pill; XTTF: Xiaotan Tongfu decoction; FZXJJZ: Fuzheng Xiaojijinzhan decoction; XYS: Xiaoyaosan; XCHT: Xiao Chai Hu Tang; SWB: Sanwu Baisan decoction; DFB: Dahuang Fuzi Baijiang decoction; ZJW: Zuojin capsule; MSD: Modified Shenlingbaizhu decoction; BXD: Banxia Xiexin decoction; TXYF: Tong-Xie-Yao-Fang; BZD: Bazhen decoction; ETSJC: Erteno-sanjie capsule; BSJPJDD: Bushen Jianpi - Jiedu decoction; QZD: Qizhen decoction; CWQ: Chang Wei Qing decoction; JSD: Chang Wei Qing decoction; BSS: Baizhu Shaoyao San.

CANCER PREVENTION

TCM possesses a comprehensive theoretical framework, placing particular emphasis on the holistic concept and syndrome differentiation, disease prevention and treatment, utilizing measures to prevent disease occurrence and their further development and progression. Previous studies have demonstrated that patients with type 2 diabetes who underwent TCM treatment for over 1 year exhibited a lower incidence of rectal cancer compared to those who did not receive such treatment[9]. Multi-center clinical studies have revealed that TCM compounds exhibit favorable efficacy in preventing the recurrence and malignant transformation of colorectal adenomatous polyps following resection[10-13].

The gut microbiota comprises a complex ecological system and plays a dual role in promoting and inhibiting tumor progression. It directly or indirectly influences CRC occurrence and development. The intestinal microbiota is closely associated with various organs in the human body, forming “gut-liver” and “lung-gut” axes that profoundly impact the immune system. TCM can regulate intestinal flora to inhibit carcinogenesis. For instance, Xianlian Jiedu decoction[14] effectively reduces inflammation, restores intestinal microbial balance , and improves metabolic disorders to inhibit colon inner wall tumor formation. Pien Tze Huang[15,16] enhances intestinal flora and metabolites while repairing intestinal barrier function. It also suppresses carcinogenic and pro-inflammatory pathways to prevent CRC by inhibiting the signal transducer and activator of transcription 3 (STAT3) pathway and regulating the transforming growth factor (TGF)-β1/zinc finger E-box-binding homeobox/miR-200 signaling network, thereby promoting cancer cell apoptosis and inhibiting proliferation and metastasis.

Specific constituents, such as curcumin[17,18], polysaccharides[19,20] (apple polysaccharide and mushroom glucan), and saponins[21,22] (Paris saponins, ginsenosides, and soy saponins) in medicinal and food homologous plants like fruits, vegetables, and spices, also exhibit preventive effects against CRC. The underlying mechanism involves modulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway, thereby inhibiting colon cancer cell proliferation and inducing apoptosis. Several healthy beverages, including green tea[23-25], have been consumed in China for millennia and are believed to possess preventive effects against CRC.

Certain Chinese medicine prescriptions can modulate the body’s immune system, exerting inhibitory effects on cancer. Notably, Yi-Yi-Fu-Zi-Bai-Jiang-San[26-29] significantly enhances mouse immunity and suppresses carcinogenesis and tumor progression. Additionally, TiaochangXiaoliu decoction[30] reduces serum levels of interferon-γ, interleukin (IL)-2, and tumor necrosis factor-α while increasing CD4(+), CD8(+), CD4(+)/CD8(+) ratios, as well as natural killer cell content in plasma. These findings highlight the potential of immune modulation in inhibiting ammonia methane/dextran sulfate sodium (DSS)-induced CRC.

Inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, is associated with a high risk of cancer development. The role of TCM in treating inflammatory bowel disease has garnered significant attention[31]. Experimental studies have established a mouse model for colitis-associated cancer transformation, where intervention with Liujunzi decoction[32] demonstrated effective inhibition of cancer transformation in inflammatory bowel disease. Berberine (BBR) can reduce colitis-related colorectal neoplasia by modulating intestinal flora and regulating short-chain fatty acid metabolism[33,34]. Shaoyao decoction[35,36], commonly used to treat inflammatory bowel disease associated with dampness and heat accumulation, exerts its therapeutic effects by regulating the Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements signaling pathway. This down-regulates pro-inflammatory cytokine release, inhibits inflammation, and prevents cell damage caused by oxidative stress. Additionally, Shaoyao decoction inhibits epithelial-mesenchymal transition (EMT) to prevent and treat inflammatory bowel diseases-related CRC. Dachengqi decoction[37] is primarily composed of flavonoids and anthraquinones, and it exhibits anti-tumor effects by potentially modulating cell proliferation and apoptosis while decreasing inflammation. Danggui Buxue Tang has been shown to possess anti-inflammatory and anti-cancer properties, potentially mitigating the inflammation-to-cancer transformation in ulcerative colitis. Additionally, Danggui Buxue Tang can enhance the efficacy of 5-fluorouracil (5-FU) by modulating the c-Jun N-terminal kinase-mediated signal transduction pathways[38,39].

PREVENTION OF CANCER INVASION AND METASTASIS

Tumor invasion and metastasis constitute a highly intricate process. The initial step involves attenuating autophagy and apoptosis, thereby enhancing cancer cell proliferation. Subsequently, this facilitates angiogenesis, enabling increased nutrient absorption by the tumor from its microenvironment and subsequently stimulating cancer cell growth.

The anti-tumor mechanism of TCM is intricate, encompassing the regulation of various signaling pathways including PI3K/Akt, nuclear factor kappa B (NF-κB), mitogen-activated protein kinases (MAPK), Wnt/β-catenin, epidermal growth factor receptor, p53, TGF-β, mTOR, Hedgehog and immune regulatory signaling pathways to modulate CRC proliferation, apoptosis, cell cycle progression, migration and invasion, as well as autophagy induction and EMT[40-42]. Moreover, it primarily focuses on the following aspects[43,44]: (1) Modulating the intestinal microorganism’s internal environment; (2) Inducing apoptosis while inhibiting proliferation; (3) Suppressing tumor metastasis; and (4) Inhibiting EMT occurrence. Additionally, it can also regulate macrophage activity and intervene in the CRC microenvironment[45], thereby regulating body lipid metabolism mechanisms[46] and exhibiting antitumor activity.

Disorders in the intestinal microbiota have been implicated in promoting tumor progression. TCM can modulate cancer progression by regulating intestinal flora composition[47-50] and structure, while altering endogenous metabolite levels. These changes subsequently impact various aspects of intestinal barriers, immune system function, and systemic metabolism, thereby exerting anti-tumor effects[51,52]. Glucose, lipids, and amino acid metabolism play a crucial role in cancer metastasis by influencing cancer cell metabolism and the tumor microenvironment (TME). TCM and its bioactive compounds hold great potential for clinical applications in treating cancer metastasis[53,54].

Inhibit cancer invasion

TCM prescriptions: The prescription of TCM is the cornerstone of its treatment approach, distinguished by its extensive clinical application over thousands of years, complex composition, and synergistic effects that target multiple aspects of health (Table 1).

Table 1 The role and characteristics of common metal nanomaterials.

Metal	Metal nanomaterials	Role of nanomaterials	Characteristics of nanomaterials	Ref.
Au	AuNPs spheres	Cytotoxicity: AuNPs stars were the most toxic, while AuNPs spheres were the least toxic. Induction of apoptosis. Drug delivery. Photothermal therapy	Small size, large specific surface area, good biocompatibility. The optical properties and cytotoxicity are shape and size dependent. Strong penetration	[19]
	AuNPs rods
	AuNPs stars
	AuNPs	Cytotoxicity. Surface plasmon resonance: AuNPs have a strong surface plasmon resonance effect, which can be detected by ultraviolet-visible spectroscopy. Medium or drug carrier for photothermal therapy	Size dependence. Biocompatibility. Cell uptake efficiency is size-dependent	[20]
	AuNPs	Enhance the effect of hyperthermia. Enhance the effect of chemotherapy. Combined therapy: AuNPs showed synergistic effect when combined with microwave hyperthermia and chemotherapy	Size dependence. Good biocompatibility. Photothermal conversion capability. Drug delivery potential	[21]
	Ph-AuNPs	Antitumor activity. Cytotoxicity. Cell cycle arrest. Induction of apoptosis	Small and uniform size. Good biocompatibility. Surface modification. High stability. Environmental protection and low cost	[22]
	“Hedgehog ball” shaped nanoprobes (Fe3O4@Au-pep-CQDs)	Detection of inflammatory markers. Multimodal imaging. Tumor microenvironment monitoring	Multi-modal detection capability. Magnetic separation function. High sensitivity and specificity. Good biocompatibility. Targeting	[23]
	Glycogenic AuNPs	Anticancer activity. Good biocompatibility. Cellular uptake	Controllable size. Surface modification. Selective toxicity. Fluorescence characteristics	[24]
	Protein-coated AuNPs	Drug carrier. Fluorescent labeling diagnosis. Enhanced cellular uptake	Controllable size and surface charge. Good biocompatibility. High cellular uptake efficiency	[25]
	B-AuNPs conjugated CIS and DOX	Drug delivery. Enhance drug stability. Reduce side effects	Good biocompatibility and low toxicity. Surface chemical properties can be adjusted. Capable of loading a large number of drug molecules. It can accumulate in tumor tissues	[26]
	Au-GSH NPs	Inhibition of tumor cell extravasation. No toxicity. Enhanced cellular uptake and accumulation	Small size, good dispersion and stability. Negatively charged surface, which facilitates cellular uptake. No toxicity	[27]
	AuNR@SiO2	Chemotherapy: DOX loading. Photothermal therapy. Anti-angiogenesis. Targeted delivery	Photothermal response. Drug carrier. Targeting. Adjustable degradation	[29]
	AuNPs functionalized carborane complex	BNCT treatment. Imaging and diagnosis. Drug delivery	Good biocompatibility. Targeting. Photothermal response. Adjustable water solubility	[30]
	PtU2-AuNPs	Drug delivery. Enhanced cytotoxicity. Targeted therapy	Biocompatibility. Drug carrier function. Enhanced cellular uptake. Enhanced cytotoxicity	[31]
	Au@MMSN-Ald	Bone-targeted therapy. Integrated chemotherapy and chemodynamic therapy. Dual-modality imaging. Responsive drug release	Versatility. Efficient drug release in the tumor microenvironment. Efficient targeting ability. Imaging ability	[32]
Ag	AgNPs	Antibacterial effect. Cytotoxicity. Induction of oxidative stress. Cell cycle regulation	High surface area. Quantum size effect. Surface effect. Size and shape dependence. Good biocompatibility	[33]
	AgNPs	Cytotoxicity. Antibacterial effect. Induction of apoptosis. Affect the cell cycle. Oxidative stress induction	High surface area. Quantum size effect. Surface effect. Size and shape dependence. Good biocompatibility. Cellular uptake capacity. Induction of oxidative stress	[34]
	AgNPs	Cytotoxicity. Antibacterial effect. Induction of apoptosis. Affect the cell cycle. Oxidative stress induction. Genotoxicity. Drug delivery vehicles	High surface area. Quantum size effect. Surface effect. Size and shape dependence. Good biocompatibility. Cellular uptake capacity. Induction of oxidative stress. Cell-specific responses	[35]
	AgNPs synthesized from plant extracts	Antimicrobial activity. Anti-proliferative activity. Drug delivery. Bioimaging	High surface area. Quantum size effect. Surface effect. Size and shape dependence. Good biocompatibility. Versatility. Environmentally friendly. Diversity of antimicrobial mechanisms	[36]
	AgNPs synthesized from leaf extracts	Antimicrobial activity. Anti-proliferative activity. Drug delivery. Bioimaging. Antioxidant activity	High surface area. Quantum size effect. Surface effect. Size and shape dependence. Good biocompatibility. Versatility. Environmentally friendly. Diversity of antimicrobial mechanisms	[37]
	AgNPs synthesized from grapefruit extracts	Antimicrobial activity. Anti-proliferative activity. Drug delivery. Bioimaging. Antioxidant activity	High surface area. Quantum size effect. Surface effect. Size and shape dependence. Good biocompatibility. Versatility. Environmentally friendly. Diversity of antimicrobial mechanisms	[38]
	AgNPs and cAgNPs synthesized by Bacillus cereus	Antimicrobial activity. Anti-proliferative activity. Drug delivery. Bioimaging. Induction of apoptosis. Reduced normal cytotoxicity	High surface area. Quantum size effect. Surface effect. Size and shape dependence. Good biocompatibility. Versatility. Environmentally friendly. Diversity of antimicrobial mechanisms	[39]
	AgNPs coating	Antibacterial property. Biocompatibility. Drug release. Surface modification	Size effect. Surface activity. Concentration dependence. Shape dependence	[40]
	f-HAp/PVP/Ag NPs	Antibacterial property. Biocompatibility. Drug release. Surface modification	Size effect. Surface can be modified. Concentration dependence. Shape dependence	[41]
Cu	Cu-Fe3O4 NCs-AS-ALG	Catalytic activity. Enhanced oxidative stress. Induction of apoptosis. Targeted delivery. Good biocompatibility	High surface area. Surface activity. Surface can be modified. Concentration dependence. Shape dependence	[42]
	Cu-Cy NPs	Photodynamic therapy. Antitumor activity. Reactive ROS generation	High surface area. Photosensitive characteristics: Microwave activation. Good biocompatibility. Versatility: Combined thermal and chemical effects	[43]
Fe	“Hedgehog ball” shaped nanoprobes (Fe3O4@Au-pep-CQDs)	Detection of inflammatory markers. Multimodal imaging. Tumor microenvironment monitoring	Multi-modal detection capability. Magnetic separation function. High sensitivity and specificity. Good biocompatibility. Targeting	[23]
	Cu-Fe3O4 NCs-AS-ALG	Catalytic activity. Enhanced oxidative stress. Induction of apoptosis. Targeted delivery. Good biocompatibility	High surface area. Surface activity. Surface can be modified. Concentration dependence. Shape dependence	[42]
	Zn-Fe3O4 NPsCo-Fe3O4NPs	Magnetic moment and magnetic anisotropy. Magnetic heating effect. Cell labeling and imaging. Drug delivery. Cell therapy. Good biocompatibility. Ion release. Cytotoxicity	High surface area. Surface activity. Concentration dependence. Magnetic properties. Shape dependence. Surface modification. Stability	[44]
	Carbon-coated iron oxide NPs	Contrast enhancement on MRI. Drug delivery. Magnetic heating therapy. Cell isolation and labeling. Cell viability and toxicity	High surface area. Surface activity. Size dependence. Concentration dependence. Good biocompatibility. Shape dependence. Surface modification. Stability	[45]
	Iron oxide NPs (IO-cage and IO-sphere)	Enhance drug loading. Enhance drug stability. Targeted therapy. Induction of apoptosis. Reduce tumor volume. Bioluminescence imaging. Immune escape	High surface area. Shape effect. Surface modification. Stability. Targeting. Good biocompatibility	[46]
	Fe3O4 NPs	Endocytosis promoted by electrical stimulation. MRI signal enhancement. Cell labeling and tracking. Magnetic heating therapy. Drug delivery	High surface area. Shape affects the endocytic mechanism. Surface modification. Targeting. Enhancing effect of electrical stimulation	[47]
	Superparamagnetic iron oxide NPs	Biomedical imaging. Magnetic thermotherapy. Biosensing and diagnostics. Support for tissue repair and regeneration. Fight infections	Small size effect. Surface effect. Quantum size effect. Macroscopic quantum tunneling. Good biocompatibility. Adjustability	[48]
	FeHA and Mag@CaP NPs	Enhanced MRI and ultrasound imaging. Drug carrier. Bone tissue repair and regeneration. Biosensors. Fight infections	Small size effect. Surface effect. Quantum size effect. Versatility. Good biocompatibility. Adjustability	[49]
	Fe3O4@ZIF-8 NPs	Improve drug targeting. Enhance drug stability. Ph-responsive release. Enhanced MRI and optical imaging. Chemotherapy intensification. Bone tissue repair and regeneration	Small size effect. Surface effect. Quantum size effect. Versatility. Good biocompatibility. Adjustability	[50]
	HA@MOF/D-Arg NPs	Improve drug targeting. Enhance drug stability. Ph-responsive release. Enhanced MRI imaging. Enhanced chemotherapy and radiotherapy. Alleviate tumor hypoxia. Bone tissue repair and regeneration	Small size effect. Surface effect. Quantum size effect. Versatility. Good biocompatibility. Adjustability	[51]
	D-Arg/GOX/TPZ@PDA/MOF NPs	Improve drug targeting. Enhance the efficacy of medications. Ph-responsive release. Enhanced MRI imaging. Enhanced chemotherapy and radiotherapy. Starvation therapy. Gas therapy. Bone tissue repair and regeneration	Small size effect. Surface effect. Quantum size effect. Versatility. Good biocompatibility. Adjustability	[52]
	FePt/MnO2@PEG NPs	Improve drug targeting. Prolong the drug circulation time. Enhanced MRI imaging. Radiotherapy enhancement. Alleviate tumor hypoxia. Induction of ferroptosis	Small size effect. Surface effect. Quantum size effect. Versatility. Good biocompatibility. Adjustability	[53]
	BTZ/TA/Fe3+ NPs	Improve drug stability. Control drug release. Enhance the efficacy of medications. Reduce side effects. Improve drug delivery efficiency	pH sensitivity. High drug loading efficiency and drug loading capacity. Good biocompatibility. Stability. Adjustability	[54]
	FeS2@CP NPs	Photothermal therapy. Chemo-dynamic therapy. Collaborative therapy. Tumor microenvironment responsiveness	Efficient Fenton catalytic activity. High photothermal conversion efficiency. Good biocompatibility. Versatility. Degradability	[55]
Ca	HA-BSA-PTX NPs	Cytotoxicity. Cell cycle arrest. Inhibition of cell migration and invasion. Promote osteoblast differentiation. Regulation of osteogenic gene expression. Reduce systemic toxicity	Efficient drug loading and release. Good biocompatibility and degradability. Versatility	[56]
	CaF2:Eu NPs	Enhance the effect of adjuvant radiotherapy. DNA damage. Inhibition of tumor growth. Reduce tumor recurrence and metastasis	Photoluminescence characteristics. Good biocompatibility. Selective toxicity. Radioenhancement characteristics	[57]
Zn	ZnO NPs	Induction of apoptosis. Induction of autophagy. Oxidative stress and cell death. Interaction between autophagy and apoptosis	Stability. Good biocompatibility. Zinc ion release characteristics. Effect on cell cycle. Selective toxicity	[58]
	ZnO NPs	Ultrasound-assisted water oxidation. ROS generation. Inhibition of tumor cell growth. Induction of apoptosis	Crystallinity. Optical properties. Piezoelectric characteristics. Catalytic activity. Surface modification and reactivity	[59]
	ZnO NPs	ROS production. Induction of apoptosis. Antitumor activity	Crystallinity. Optical properties. Green synthesis, environmental protection and low cost. Surface chemical properties	[60]
	ZnTiO3 NPs	Antibacterial. ROS generation. Cytotoxicity	Broad-spectrum antibacterial activity. Mechanical properties. Good biocompatibility	[61]
	Ti-ZnO-PBA-NG NPs	Antibacterial. Increased intracellular ROS levels. Induction of tumor cell apoptosis. Inhibition of tumor cell proliferation. Promote the proliferation and differentiation of osteoblasts	pH responsiveness. Antibacterial property. Anti-tumor properties. Good biocompatibility. Surface modification	[62]
	ZnO NPs synthesized from Rehmannia	Anticancer activity. Induction of apoptosis. ROS production. Mitochondrial membrane potential changes	Green synthesis. Good biocompatibility. Crystal structure. Bioactive ingredients. Photocatalytic activity	[63]
Ti	TiO2 NPs	Acoustic catalytic activity. ROS produced. Inhibition of tumor cell growth and proliferation	Semiconductor properties. Amorphous structure. Optical inertia	[59]
	ZnTiO3 NPs	Antibacterial. ROS generation. Cytotoxicity	Broad-spectrum antibacterial activity. Mechanical properties. Good biocompatibility	[61]
	TiO2 NPs	Induction of cytotoxicity. ROS production. Decrease GSH levels	Large surface area. Semiconductor properties. Good biocompatibility. Photocatalytic activity	[69]
	TiO2 NPs	Photocatalytic activity. Efficient generation of ROS under microwave. Selective toxicity. Microwave induced photodynamic therapy. Inhibition of osteosarcoma tumor growth	Clear lattice stripes. Surface charge. Good biocompatibility. Stability	[70]
	TiO2 NPs	Broad-spectrum antibacterial property. Cytotoxicity. Photocatalytic performance	Green synthesis, low environmental protection cost. Tetragonal crystal structure. Optical properties. Chemical stability	[71]
	TiO2 NPs	Broad-spectrum antibacterial property. Antitumor activity. ROS production. Application of bioanalog scaffolds. Biological activity. Mechanical properties. Protein adsorption capacity	Anatase phase structure of tetragonal crystal system. Low environmental cost. Photocatalytic activity. Thermal stability	[72]
	Fluorescent TiO2 NPs	Broad-spectrum antibacterial property. ROS produced. Drug carrier. Intracellular drug tracking and fluorescence imaging	Green synthesis, low environmental protection cost. Surface charge. Fluorescence characteristics. High drug load	[73]
	F-TiO2/P and F-TiO2/PC	Photothermal effect and photocatalytic effect. ROS production. Promote osteogenic differentiation. Antitumor activity	Good photothermal stability. Good photocatalytic performance. Hydrophilicity. Multifunctional integration. Surface modification	[74]
	TiO2 NPs	Photocatalytic degradation. Cytotoxicity. Photodynamic therapy. Antibacterial property. Oxidative stress	Photocatalytic activity. High specific surface area. Be versatile	[75]
	Folic acid modified TiO2 NPs	Cytotoxicity. Generation of ROS. Induction of apoptosis. Enhanced cellular uptake	Good dispersion. Tumor targeting. Surface charge	[76]
Pt	PtU2-AuNPs	Drug delivery. Enhanced cytotoxicity. Targeted therapy	Biocompatibility. Drug carrier function. Enhanced cellular uptake. Enhanced cytotoxicity	[31]
	FePt/MnO2@PEG NPs	Improve drug targeting. Prolong the drug circulation time. Enhanced MRI imaging. Radiotherapy enhancement. Alleviate tumor hypoxia. Induction of ferroptosis	Small size effect. Surface effect. Quantum size effect. Versatility. Good biocompatibility. Adjustability	[53]
	ALN-PtIV-Lipo	Enhance the effect of chemotherapy. Inhibits bone destruction. Targeted delivery. Drug accumulation. Tumor growth inhibition	Stability. Targeting. Good biological safety. Drug release	[77]
Sr	Sr-HA NPs	Promote bone regeneration. Improve cell activity. Drug delivery	Stability. Surface charge. Good biocompatibility	[78]
Ir	IrO2@ZIF-8/BSA-FA	Photothermal therapy. Photodynamic therapy. Improve the efficiency of cancer treatment. Tumor targeting. Alleviate tumor hypoxia	Versatility. Photothermal conversion capability. Catalase like activity. Targeting. High drug loading capacity. Dual pH/NIR responsiveness. Good biocompatibility	[90]
	BSA-IrO2 NPs	Chemotherapy drug carrier. Photothermal therapy. Collaborative therapy. Increase circulation time. Tumor targeting	Stability. Photothermal conversion capability. High drug loading capacity. Dual pH/NIR responsiveness. Good biocompatibility	[91]

BNCT: Boron neutron capture therapy; MRI: Magnetic resonance imaging; ROS: Reactive oxygen species; GSH: Glutathione.

The primary constituent of Gegen Qinlian decoction[51,55] is Radix Pueraria[56], and its active compound is puerarin[57,58], which both exhibit significant anti-tumor effects. The underlying mechanisms involve modulation of the intestinal microbiota and alteration of the TME. Small bupleurum decoction, known as Xiao Chai Hu Tang[59,60], modulates the gut microbiota and regulates the Toll-like receptor 4/myeloid differentiation marker 88/NF-κB signaling pathways, thereby restoring intestinal flora balance by reducing the abundance of pathogenic bacteria, algae, and mucor. This intervention improves the luminal environment and exhibits antitumor and anti-anxiety properties. Xiaoyaosan[61] regulates the abundance of Bacteroides, Lactobacillus, Desulfovibrio, and Ricinidae in the intestine to ameliorate dysbiosis and effectively mitigate CRC progression in CRS-treated mice. Sanwu Baisan decoction[62] demonstrates potent antitumor efficacy in CRC mice by enhancing the secretion of anti-tumor immune cytokines, inducing cancer cell apoptosis, maintaining intestinal microbiota homeostasis, and inhibiting tumorigenesis via modulation of the Toll-like receptor 4/cyclooxygenase-2 (COX-2)/prostaglandin E2 pathway.

Recently, Dahuang Fuzi Baijiang decoction[63] was shown to inhibit the production of C-C motif ligand 2 and protect Tex+ progenitor cells in the obese microenvironment, thereby impeding CRC progression. Zuojin capsule[64,65] has been widely used to treat CRC due to its ability to target CDKN1A, Bcl2, E2F1, PRKCB, MYC, CDK2 and matrix metalloproteinase-9 (MMP9). Additionally, it inhibits the 5-HTR1D-Wnt/β-catenin signaling pathway. Shenlingbaizhu powder and its Modified Shenlingbaizhu decoction[66] effectively suppress CRC growth by inhibiting TGF-β-induced EMT. The anti-tumor mechanism of Banxia Xiexin decoction[67] involves targeting ferroautophagy mediated by the PI3K/AKT/mTOR axis. This leads to intracellular iron accumulation and generation of reactive oxygen species, ultimately resulting in ferroptosis. Tong-Xie-Yao-Fang[68] can inhibit tumor growth in CRC mice by stimulating immune responses by inhibiting hypothalamic-pituitary-adrenal axis hormone secretion and promoting mature dendritic cell activation and T cell function. Bazhen decoction[69] can reverse the abnormal expression of genes such as PI3K, AKT, MYC, epidermal growth factor receptor, hypoxia-inducible factor 1α (HIF-1α), VEGF receptor (VEGFR), JUN, STAT3, CASP3, and TP53, and regulate signaling pathways such as PI3K-AKT, P53, and VEGF to inhibit CRC progression.

TCM extract or monomer composition: Many active TCM ingredients hold potent anti-CRC activity, as demonstrated by experimental studies[3]. Notably, common compounds such as flavonoids and phenolic acids have significant anticancer effects. These bioactive components influence CRC progression through multiple mechanisms, including the regulation of molecular and signaling pathways, modulation of gut microbiota, and targeting of cancer stem cells (CSCs), all of which are critical in CRC pathogenesis.

Resveratrol, a natural compound found in grapes[70], can inhibit CRC EMT by modulating the TGF-β1/Smad signaling pathway and q/E-calcium protein. Additionally, it enhances autophagy-related cell apoptosis in CRC. Curcumin[71-73], the principal bioactive constituent of ginger with medicinal and dietary origins, possesses a rich pharmaceutical history in treating intestinal diseases. It can disrupt EMT by promoting HIF-1α degradation, inhibit CRC cell invasion and migration, and induce cell cycle arrest and apoptosis by suppressing glutaminase 1-mediated glutamine metabolism. Additionally, curcumin can enhance the anti-cancer efficacy of chemotherapeutic agents and exhibit a synergistic effect with Astragalus extract[18]. Its mechanism of action involves effectively reversing PI3K/Akt pathway activation, reducing intestinal inflammation and improving intestinal barrier function.

Additionally, mignonette and luteolin[74,75] can inhibit the MAPK pathway in CRC cells, decreasing cell proliferation, inducing cell cycle arrest, apoptosis and DNA damage progression. Moreover, they can also inhibit CRC metastasis by regulating the miR-384/PLEKHM1 axis. On the other hand, quercetin[76-81] exhibits potent anticancer activity through several signaling pathways, including MAPK/extracellular regulated kinase 1/2 (ERK1/2), p53, Janus kinase (JAK)/STAT and TNF-related apoptosis-inducing ligand, AMP-activated protein kinase α1/apoptosis signal-regulating kinase 1/p38 as well as receptor for advanced glycosylation end products/PI3K/AKT/mTOR. It also affects the high mobility group box 1 and NF-κB signaling pathways, along with Nrf2-induced signaling pathways, resulting in cell cycle arrest and subsequent death of CRC cells[81].

The plant-derived benzyl xenobiotic BBR[82] is a novel multi-target receptor tyrosine kinase inhibitor exhibiting potent activity against various malignant tumors, including CRC. It effectively suppresses cell proliferation, invasion, and metastasis while inducing apoptosis, regulating cell metabolism, blocking cell cycle progression, inhibiting angiogenesis and enhancing chemosensitivity. Studies have demonstrated that BBR can inhibit CRC cell growth, migration, invasion and colony formation without exerting toxicity on normal colon cells[83]. Moreover, in vitro experiments reveal its ability to induce apoptosis and cell cycle arrest at G(0)/G(1) in CRC cells, along with attenuated Hedgehog signaling pathway activity. Furthermore, BBR may prevent high fat diet-induced CRC by modulating intestinal microbiota-mediated lysophosphatidylcholine metabolism[84]. Additionally, it impedes CRC invasion and metastasis by inhibiting receptor tyrosine kinases/Akt axis expression[85], COX-2/prostaglandin E2-JAK2/STAT3 signaling pathway activation, and by downregulating helix-loop-helix transcription factor with YRPW motif 2 hub gene expression and metastasis-related proteins E-cadherin β-catenin[86] and cyclin D1 levels[87]. The antitumor activity of matrine and sophocarpine[88] has been investigated in various cancers, including CRC. Their mechanism of action involves interference with the miR-10b/phosphatase and tensin homolog deleted on chromosome 10 pathway[89], down-regulation of p53 and checkpoint kinase 1 expression[90], regulation of β-catenin/c-Myc signaling, and inhibition of the mitogen-activated protein kinase kinase/ERK/vascular endothelial growth factor (VEGF) pathway to disrupt metabolic reprogramming and EMT in hepatocellular carcinoma[91]. Other TCM and food extracts, including toosendanin[92], raddeanin A[93], and allicin[94], exhibit comparable anti-CRC effects.

Saponins are the primary constituents of numerous herbal medicines that exhibit inhibitory effects on CSCs. Compounds such as ginsenoside[95-97], Paris saponin VII[98], active ingredients in Rhizoma Paridis[99], notoginsenoside[100], and naringin[101] can suppress CRC cell growth and proliferation, induce apoptosis, and inhibit essential signaling pathways, including IL-6/STAT3 and Akt/mTOR/p70S6K, among others. Monotropein[102] exerts its anti-tumor effects by inhibiting the cell cycle, inducing apoptosis, and suppressing cell migration. Astragaloside[103] and its extract[104] also possess potent anti-CRC properties, which are associated with the regulation of the circ_0001615 and miR-873-5p/LIM and SH3 protein 1 axis. Additionally, these compounds can inhibit CRC metastasis by reducing extracellular vesicle release and suppressing M2-type tumor-associated macrophage activation[105]. Echinacoside[106] exhibits anti-tumor metastatic effects by promoting the growth of butyrate-producing gut bacteria, which subsequently down-regulates PI3K/Akt signaling and EMT.

The anti-tumor effect of paeoniflorin[107,108] may be attributed to its ability to inhibit the IL-6/STAT3 signaling pathway and reduce IL-17 levels. Additionally, it can regulate the miR-3194-5p/CTNNBIP1/Wnt/β-catenin axis to suppress CRC cell stemness. Moreover, paeoniflorin can impede CSC migration and invasion by downregulating histone deacetylase 2 expression, thereby reversing EMT and modulating cellular levels of E-cadherin and vimentin, ultimately leading to potent anti-tumor effects. Artesunate[109] and ziyuglycoside II[110] both suppress CRC cell proliferation by inducing reactive oxygen species-dependent cellular senescence and autophagy.

Plant-derived pentacyclic triterpenoids such as betulinic acid[111] and ursolic acid exhibit significant anti-tumor activity and hold promise in CRC prevention and treatment. The latter can induce caspase-dependent apoptosis, focal adhesion kinase/PI3K/Akt single spring cleavage, and EMT-related anoikis in human colorectal tumor cells. Inhibition of EMT[112] and Smoothened activates Akt signaling dependence, independent of the canonical Hedgehog pathway[113], regulating the miR-140-5p/TGF-β3 axis to suppress Wnt/β-catenin signaling pathway activation[114] and thereby inhibiting CRC cell proliferation and cell cycle progression while promoting cellular apoptosis. Glycyrrhizic acid can inhibit CRC progression through the AKT1/ERK1/2-glycogen synthase kinase-3β-β-catenin signaling pathway[115]. Additionally, glycyrrhizic acid can attenuate Musashi homolog 2-mediated immunopathology and immune infiltration in CRC in vitro and in vivo by inhibiting sirtuin 3 and blocking high mobility group box 1 activity[116,117]. Furthermore, it reduces the formation of neutrophil extracellular traps by inhibiting peptidylarginine deaminase 4, thereby improving colitis-associated CRC[118].

Triterpene compounds derived from Rhus chinensis extract[119,120] can effectively suppress glycolysis and glutamine pathways by targeting key enzymes including Enolase 1, aldolase A, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, pyruvate kinase M2, and lactate dehydrogenase A to inhibit CRC. Furthermore, triterpene significantly impedes CRC cell growth and invasion by inhibiting the acid-sensing ion channel 2-induced calcineurin/nuclear factor of activated T cells pathway. Known for its spleen-strengthening and qi-replenishing properties, Jujube extract containing bioactive triterpenes[121] alleviates colorectal pixu (spleen deficiency)-associated inflammation, while also exerting an inhibitory effect on CRC via modulation of the PI3K/Akt/NF-κB signaling pathway.

Cucurbitacin B[122] can target the JAK2/STAT3 signaling pathway in CRC, thereby controlling M2 macrophage polarization and inhibiting CRC invasion and metastasis, similar to the anti-CRC effects observed with the active components of Yunnan Gargaria (YAT-17)[123,124]. Emodin, a primary constituent of TCM rhubarb, suppresses CRC proliferation and invasion by inhibiting acyl-coenzyme A synthetase long-chain family member 4 and reducing VEGF secretion and VEGFR1/VEGFR2 expression[125-127]. Additionally, emodin induces CRC cell ferroptosis via nuclear receptor coactivator 4-mediated ferritinophagy and NF-κB pathway inactivation. Shikonin, a natural quinone compound[128], possesses anti-tumor properties and can prevent acute ulcerative colitis. It upregulates 70 kDa heat shock protein to enhance immunogenicity and improve the effectiveness of programmed death receptor 1 (PD-1) blockade in CRC. Shikonin’s anti-tumor mechanism involves targeting IL6 and inhibiting the IL6R/PI3K/Akt signaling pathway, which curtails CRC cell proliferation, migration, and invasion while promoting apoptosis[129]. Total coumarins inhibit colorectal tumor growth by modulating exosome microRNA expression and CSC angiogenesis and by inducing apoptosis and autophagy[130,131].

Kras-mutant cancers exhibit heightened vulnerability to iron-dependent cell death, specifically ferroptosis, which is driven by lipid peroxidation. Osthole exerts its anti-cancer effects in KRAS-mutated CRC cells by inhibiting the AMP-activated protein kinase/Akt/mTOR signaling pathway, thereby promoting iron dislocation[132]. Similarly, erianin[133-136] suppresses CRC tumor growth and metastasis through autophagy-dependent siderosis, modulating the TMPO-AS1/miR-126-3p/PIK3R2 axis and inactivating the PI3K/Akt signaling pathway. Alizarin mollugin[137] curtails CSC proliferation and induces ferroptosis by targeting the insulin-like growth factor (IGF) 2 mRNA binding protein 3/peroxiredoxin 4 axis. Sinomenine[138], a bioactive alkaloid from TCM, inhibits cancer cell proliferation via reactive oxygen species production, ferritin phagocytosis, and iron deposition.

The Wnt/β-catenin signaling pathway is a well-established driver of colon cancer. However, targeted therapies against the pathway have not yet reached clinical application. The natural compound liquidambaric acid[139] directly targets tumor necrosis factor receptor-associated factor 2, inhibiting oncogenic Wnt/β-catenin signaling both in vitro and in vivo, and suppressing CSC growth. Neolignan[140], an extract from Rhizoma radix, also interferes with CRC development by inhibiting the Wnt/β-catenin signaling pathway. Black raspberry anthocyanins[141] upregulate miR-24-1-5p expression in human CSCs, significantly reducing β-catenin levels and curtailing tumor cell proliferation, migration, and survival. Polysaccharides[19], important functional phytochemicals found abundantly in TCM, possess anti-CRC effects by regulating intestinal flora imbalance and modulating the Wnt pathway[20].

Morusinol[142,143], a compound extracted from mulberry plants, exerts its therapeutic effects on CRC by mediating cholesterol biosynthesis through Forkhead box O-3a nuclear aggregation inhibition, thereby suppressing cell proliferation and inducing autophagy. Ethyl cinnamate[144] suppresses CRC angiogenesis and tumor growth by modulating the VEGFR2 signaling pathway.

TCM and Chinese patent medicine: CSC is closely associated with high tumorigenicity, chemotherapy/radiotherapy resistance, and metastasis and recurrence, particularly in CRC. The chemical composition of TCM is complex. Both individual TCM herbs and their isolated components[42,145] exhibit multi-target and multi-pathway effects similar to those of TCM compounds. Polysaccharides from Astragalus[103], Ginseng[146], Ganoderma lucidum[147], Dendrobium officinale[148], Puerariae Radix[149], and other TCM herbs can inhibit or kill tumor cells indirectly by enhancing immune function or directly by inducing tumor cell differentiation or apoptosis, as well as by modulating oncogene expression[19,150]. Furthermore, these polysaccharides exhibit synergistic effects with radiotherapy, chemotherapy, and immunotherapy[151]. Azalea Rhododendron molle G. Don[152] contains 17 types of anticancer bioactive compounds that induce CSC apoptosis and inhibit migration.

Salvia miltiorrhiza and its extract tanshinone exhibit potent anti-colorectal tumor activity by up-regulating 70 kDa heat shock protein to enhance immunogenicity and improve the efficacy of PD-1 blockade in CRC. Furthermore, their anti-tumor mechanism involves the regulation of the INS/SRC/IL6 pathway[153], phosphorylation of target Akt1 to modulate the PI3K/Akt signaling pathway for promoting mitochondrial fission[140], and activation of the c-Jun N-terminal kinase/mitochondrial fission factor signaling pathway[154].

Some Chinese patent medicines, such as compound Chinese medicine injections and oral preparations manufactured using modern processes, represent the integration of TCM with contemporary pharmaceutical technology. These formulations have been utilized in clinical practice for many years; however, further evidence-based research is necessary to fully establish their efficacy and safety[155,156].

Venenum Bufonis[157,158] is the primary constituent of bufonis that inhibits CRC growth and metastasis by suppressing the NF-κB, PI3K/Akt pathways and the HIF-1α/stromal cell-derived factor-1α-CXC chemokine receptor 4/PI3K/Akt signaling pathway. It also reduces VEGF synthesis and release and degrades type IV collagen[159]. Furthermore, Venenum Bufonis targets the SRC-3/MIF pathway in chemoresistant cells to enhance chemosensitivity[160,161], regulates M2 macrophage polarization in CRC[162], inhibits the C-Kit/Slug axis involved in CRC stemness, and suppresses the STAT3 signaling pathway to counteract CRC metastasis mediated by cancer-associated fibroblasts[86,163]. Additionally, compound matrine injection exhibits anti-CSC and anti-liver metastasis effects by intervening in metabolic reprogramming and EMT of CRC and hepatocellular carcinoma through regulation of the β-catenin/c-Myc signaling pathway and induction of cell cycle arrest[90,91]. Erteno-sanjie capsule[164] has demonstrated therapeutic efficacy against CRC by positively regulating cell migration, protein phosphorylation, and the PI3K/Akt signaling pathway.

Acupuncture therapy: As a complementary therapy, acupuncture or electropuncture (EA) has been extensively used to treat various inflammation-related diseases such as obesity, ulcerative colitis, tumors, and CRC. Notably, EA has demonstrated its potential in regulating the sirtuin 1-mediated miR-215/Atg14 axis by suppressing inflammation and promoting autophagy in mouse models[165]. These mechanistic insights shed light onto the anti-CRC effects of EA and highlight its promising therapeutic candidacy; however, high-quality randomized controlled trials remain scarce.

Inhibition of post-surgical recurrence and metastasis

Postoperative recurrence of CRC significantly impacts treatment outcomes. A compound composed of Baizhu, Yinchen, Chenpi, and Fuling[166] can modulate tumor-infiltrating immune cells and hypoxia-related gene expression by downregulating the mRNA levels of BCL2 L1, XIAP, and TOP1, thereby reducing metastasis and recurrence in post-operative patients with stage II-III CRC. TCM has demonstrated potential in enhancing the overall condition by extending survival time and improving the quality of life for patients with stage IV CRC with liver and lung metastasis[167-170].

Dahuang Zhechong Pill[171] exerts inhibitory effects on CRC liver metastasis by suppressing the C-C motif ligand 2-mediated M2 polarization and improving the profibrotic microenvironment. Obesity disrupts IGF secretion and exacerbates CRC, whereas Xiaotan Tongfu decoction[172] hinders CRC liver metastasis by upregulating IGF-1/IGF-1R secretion and downregulating IGF binding protein 3 secretion. Fuzheng Xiaojijinzhan decoction[173] impedes CRC liver metastasis through the vitamin D receptor/TGF-β/Snail1 signaling pathway. Kaempferol[174] binds to HNRNPK and HNRNPL to regulate circ_0000345 and mediate the JMJD2C/β-catenin signaling pathway, thereby inhibiting CRC metastasis. It also exhibits favorable attenuation and synergistic effects when combined with chemotherapy drugs. Additional studies have demonstrated that as an external treatment with TCM characteristics, moxibustion can inhibit CRC liver metastasis by remodeling the disrupted intestinal microbial community structure, suggesting its potential as a complementary and alternative therapy for these patients[175].

SYNERGISTIC EFFECT WITH RADIATION AND CHEMOTHERAPY, TARGETED THERAPY, AND IMMUNE THERAPY

TCM combined with radiotherapy and chemotherapy

Chemotherapy is a primary therapeutic approach for CRC; however, the cytotoxic effects of chemotherapy drugs, such as bone marrow suppression, digestive dysfunction, and hand-foot syndrome, often significantly impact treatment efficacy and sustainability while posing potential life-threatening risks to patients. Additionally, chemoresistance remains an inevitable challenge in clinical practice. TCM presents a promising alternative in addressing these concerns. Furthermore, various compounds[176], extracts[177], and Chinese patent medicines[178] including formulations[155,179] have been extensively employed in clinical settings for numerous years with validated safety and efficacy profiles.

5-FU is the most commonly used adjuvant chemotherapy for CRC. It exerts a potent cytotoxic effect on tumor cells. However, prolonged administration of 5-FU increases the risk of hematologic side effects and promotes the development of drug resistance in tumor cells. TCM containing Villosol from sauce grass and its extract Patrinia villosa Juss[180] can inhibit CDKN2A gene expression and regulate the TP53-PI3K/Akt signaling axis to reverse 5-FU resistance. Similar effects have been observed with ginsenoside Rg3[181].

Additionally, Zhengyuan jiaonang[182] inhibits CT26CRC tumor growth and enhances the efficacy of combination chemotherapy while reducing its cytotoxicity. Its mechanism involves promoting tumor fibrosis, inhibiting angiogenesis, migration and invasion, as well as modulating the tumor immune microenvironment. Pulsatilla decoction[183] exhibits similar effects by deactivating STAT3. Bioactive compounds derived from SangGui grass L[184] demonstrate strong activity against both 5-FU-sensitive and resistant CRC cells by inducing apoptosis and autophagy-mediated cell death and suppressing the Wnt signaling pathway to arrest cell cycle progression at the G0-G1 phase, thereby inhibiting CRC proliferation. Furthermore, other TCM compounds exhibit promising effects in alleviating certain chemotherapy drug-induced complications such as leukopenia[185].

The neurotoxicity of oxaliplatin can readily induce hand-foot syndrome, particularly when combined with 5-FU. The combination of Bushen Jianpi - Jiedu decoction[186] and its extract raddeanin A[93] with oxaliplatin exhibits superior therapeutic effects compared to the latter alone; however, its mechanism is complex. Bushen Jianpi - Jiedu decoction regulates 559 genes and 11 proteins. Within this compound, seven bioactive compounds interfere with 39 potential targets and modulate multiple signaling pathways, including MAPK, PI3K-Akt, and HIF-1. Identifying the optimal drug dosage is a crucial aspect of developing new Chinese medicine formulations and poses a considerable challenge in the integration of traditional Chinese and Western medicine in clinical practice.

Multiple studies have shown that acupuncture and moxibustion can effectively prevent and treat the toxic effects of chemotherapeutic agents like oxaliplatin, which often cause chemotherapy-induced peripheral neuropathy[187-193]. Commonly used acupoints include Hegu (LI 4), Neiguan (PC 6), Quchi (LI 11), Taichong (LR 3), Sanyinjiao (SP 6), and Zusanli (ST 36). The therapeutic mechanisms involve inhibiting the release of inflammatory factors and blocking the binding of related receptors. Bee venom acupuncture[194] has exhibited synergistic effects with morphine, providing potent and sustained analgesia for oxaliplatin-induced neuropathic pain. This effect is associated with the modulation of spinal opioid receptors and 5-HT3 receptors, as well as the regulation of action potential thresholds in A-fiber dorsal root ganglia neurons. For instance, the anticancer efficacy of varying concentrations of Huangqin decoction and irinotecan exhibits significant differences[195].

Combined application with radiotherapy

Radiotherapy is an important modality in CRC treatment. However, tumor cells ultimately develop resistance to radiotherapy, and there are currently no effective countermeasures. Most patients with colorectal tumors ultimately die from local recurrence after developing resistance to radiotherapy. Studies have shown that ginsenoside Rg3[96] and allicin[196] can enhance CRC radiosensitivity by inhibiting NF-κB and NF-κB-regulated gene products, thereby inhibiting tumor growth and prolonging the lifespan of CT-26 xenograft tumors in nude mice. Curcumin[71,197] can promote the sensitivity of human CRC to radiochemotherapy, and its mechanism may be related to the downregulation of DNA repair-related genes such as LIG4, PNKP, and XRCC5, as well as the upregulation of CCNH. External therapies such as acupuncture[198] have demonstrated significant efficacy in alleviating chemotherapy-induced peripheral neuropathy. In addition, certain palliative functional exercise methods, such as Baduanjin Qigong[199], have significantly alleviated the fatigue associated with adjuvant chemotherapy following CRC surgery.

TCM combined with targeted and immune therapy

PD-1/programmed death ligand 1 (PD-L1) inhibitors have demonstrated significant clinical advancements. However, monotherapy with PD-1/PD-L1 inhibitors in patients with microsatellite stability (MSS) CRC exhibits a lower objective response rate and susceptibility to tumor drug resistance, necessitating combination therapy with other immune therapies, chemotherapy, radiation therapy or alternative approaches to enhance patient response rates. Nevertheless, these combined treatments often lead to the accumulation of toxic side effects. TCM represents a potential adjunctive option due to its relatively minimal adverse effects and ability to reshape the intestinal microbiota and TME in MSS CRC patients, thereby enhancing immune potency and protecting intestinal barrier function. Consequently, TCM can augment the efficacy of PD-1 blockade in CRC patients[48,51,200].

Previous studies have demonstrated that cupping electroacupuncture can have an anti-tumor effect[201]. Furthermore, it enhances the anti-tumor immune response by elevating lymphocyte and granzyme B levels and activating the stimulator of interferon genes pathway. Combination therapy with cupping electroacupuncture and PD-1 blockade yields superior therapeutic efficacy compared to monotherapy in MSS mouse models of CRC.

Combining Salvia miltiorrhiza Bunge aqueous extract[202] with anti-PD-1 antibody has demonstrated enhanced therapeutic efficacy compared to monotherapy in controlling MC38 xenograft tumors in nude mice, suggesting its potential as an immunomodulatory strategy to augment the clinical effectiveness of anti-PD-1 treatment in MSS CRC. Ganoderma lucidum polysaccharide, an extract from Ganoderma lucidum[151], significantly inhibits CRC growth and activates anti-tumor immunity. Moreover, its combination with PD-1 inhibitors further enhance the efficacy of anti-PD-1 immunotherapy. In conjunction with ginsenoside Rg1, rosmarinic acid suppresses colon cancer metastasis by co-inhibiting the COX-2 enzyme and the PD-1/PD-L1 signaling pathway[203]. Sauchinone[204,205] exhibits inhibitory effects on various tumor cells, particularly CRC cells, by downregulating MMP2 and MMP9 expression and mediating checkpoint inhibition via the PD-1/PD-L1 axis. Additionally, combinations of certain TCM components, such as carbenoxolone-ganolol and baicalin[206], demonstrate synergistic anticancer potential and enhance the efficacy of anti-PD-1 immunotherapy in CRC by inducing GSDME-dependent pyroptosis. Individual TCM compounds, like the active ingredients in Saffron, can reduce inflammatory factor expression through the IL-17 signaling pathway, thereby improving the tumor immune microenvironment and enhancing the effectiveness of immunotherapy for CRC[207].

Several TCM compounds have demonstrated comparable efficacy. Qizhen decoction[208] exerts a similar effect. It augments the abundance of Akkermansia, facilitating dendritic cell maturation for IL-12 release, activating the JAK2/STAT4 pathway, and inducing effector T cell activation. Jianpi Jiedu Recipe[209] can inhibit colon cancer proliferation and reduce PD-L1 expression via incomplete autophagy induced by reactive oxygen species, thereby exerting a synergistic immune therapeutic effect. Chang Wei Qing decoction[210] can modulate the tumor immune microenvironment by altering the intestinal microbiota, thus enhancing the efficacy of PD-1 inhibitor therapy. When combined with PD-L1 inhibitors, Jiedu Sangen decoction[211] can reverse EMT in rectal cancer cells through the PI3K/Akt signaling pathway, significantly inhibiting CRC cell migration and invasion.

TCM in combination with targeted therapies, such as bevacizumab plus FOLFIRI regimen along with ginsenoside-modified nanostructured lipid carriers containing curcumin for treating unresectable metastatic CRC, improves long-term survival rates, tolerability, and safety[212]. However, these studies are limited by small sample sizes, lack of long-term follow-up data, unblinded methodologies, and single-center designs, which hinder their ability to provide high-quality evidence for clinical application.

TCM IN FUNCTION RECOVERY

Recovery of postoperative intestinal obstruction or gastrointestinal dysfunction

Gastrointestinal dysfunction or postoperative intestinal obstruction is a prevalent complication following CRC surgery. Numerous studies have demonstrated that acupuncture holds significant potential as a therapeutic intervention for promoting gastrointestinal function recovery in patients with CRC after surgery[213-215]. Commonly employed acupuncture techniques encompass electroacupuncture and transcutaneous electrical stimulation[215-218], conventional acupuncture[219], moxibustion, scalp acupuncture, and auricular point stimulation[220]. The frequently utilized acupoints include lower He-point[216] and Zusanli[221], which exert their mechanism of action by inhibiting miR-222 up-regulation and blocking c-kit mRNA/protein and endothelial nitric oxide synthase mRNA down-regulation.

TCM prescriptions can promote postoperative intestinal obstruction recovery and synergize with modern medical rapid rehabilitation technology[222]. Among them, Daikenchuto decoction[223] is one of the most extensively studied prescriptions, and it can regulate the body’s nervous system, immune system, and inflammatory response[224]. Other prescriptions such as Shenhuang plaster[225] can significantly improve patients’ postoperative intestinal obstruction-induced inflammatory response while promoting gastrointestinal motility recovery. This may be through macrophage polarization through PI3K/Akt/NF-κB signaling pathway. Wuda granule[226] and Xiangbin prescription[227] also exhibit similar effects.

Treatment of low anterior resection syndrome

Low anterior resection syndrome is a prevalent complication in radical surgery for low rectal cancer. Defecation dysfunction, including constipation and increased defecation frequency, are the most common symptoms. However, modern medicine lacks effective treatments and mainly relies on symptomatic management. TCM treatment has shown promising results in effectively alleviating related symptoms[228]. Modified Baizhu Shaoyao San[229] can improve postoperative stool frequency without significant side effects. Acupuncture has demonstrated potential in ameliorating various symptoms associated with anterior rectal resection and holds promise as an effective intervention[228,230,231]. Nevertheless, high-quality randomized controlled trials are still lacking, and further research is needed to elucidate its mechanism of action.

Relieve postoperative depression and fatigue

Depression and anxiety can contribute to cancer development and significantly impact patients’ postoperative recovery following CRC surgery. Therefore, implementation of perioperative antidepressant interventions is imperative. TCM has been explored in this domain, with commonly employed approaches including acupuncture[232,233], Xiao-Chai-Hu-Tang, and other TCM prescriptions[60]. These interventions have demonstrated effective improvement in perioperative patients’ anxiety levels[233]; however, limited research exists.

After CRC surgery and chemotherapy, patients frequently experience spleen-stomach qi deficiency, resulting in compromised immune function and persistent fatigue. Buzhong Yiqi decoction[234] enhances immune function, thereby regulating inflammatory responses and metabolic processes to promote overall immunonutrition and restore bodily balance. Studies on acupuncture and moxibustion[235] have also confirmed the efficacy of these perioperative treatments, which are predominantly utilized for rehabilitating organ functions, including gastrointestinal, urinary, and sexual functions[236].

Application of personalized TCM syndrome differentiation treatment

TCM emphasizes individualized treatment, with syndrome differentiation and treatment forming its core principle. It posits that different diseases can be treated with the same drug based on patient-specific conditions, while the same disease requires varying therapeutic approaches at different stages. This aligns with the concept of precision medicine in modern healthcare. However, TCM syndrome differentiation often lacks objective indicators, posing significant challenges for its integration with modern medicine. This remains an active area of research[237-239]. Several studies have attempted to distinguish different TCM syndromes of CRC by analyzing variations in gut microbiota, and five specific microbiotas have been identified as potential CRC markers: Dialister sp Marseille P5638, Oscillospirales, Selenomonadaceae, Dialister, and Akkermansia muciniphila. These TCM syndrome differentiation markers are anticipated to provide a biological foundation for precise syndrome differentiation in CRC[240,241]. Additionally, characteristics of the tongue microbiome[242], immunoglobulin lambda binding 3 and nuclear morphology parameters (such as nuclear texture, eccentricity, size, and pixel intensity)[243], along with metabolite differences and characteristic metabolic pathways, are included as objective indicators to facilitate accurate and objective syndrome differentiation and TCM treatment for CRC patients[244]. Therefore, in-depth research and exploration of the objective material differences between different TCM syndromes will provide new approaches for further studies on individualized treatment of CRC with TCM[245].

CONCLUSION

As one of the most significant complementary and alternative medicines worldwide, TCM has been clinically validated for its role in preventing and treating CRC and in promoting postoperative rehabilitation. TCM exhibits characteristics such as multi-target effects and relatively low side effects. However, the complexity of TCM components, particularly animal-based medicines that primarily consist of proteins, makes them susceptible to physical factors like processing and decoction. Although network pharmacology and molecular docking technology offer potential avenues for further research on TCM, there remain unresolved challenges that currently hinder the objective assessment and recognition of TCM’s efficacy. While considerable progress has been made in studying TCM extracts due to their relative ease of control, a major limitation is their inability to reflect the core principles underlying syndrome differentiation-based treatment in TCM. Additionally, identifying efficient monomeric compounds from the vast array of TCM components poses a formidable challenge.

TCM syndrome differentiation and treatment constitute an integral and pivotal component of TCM theory, serving as a guiding principle for the development of personalized therapeutic approaches. TCM syndrome differentiation and treatment is an essential component of TCM theory, guiding the design of personalized therapies. The TCM syndrome type encapsulates the comprehensive characteristics of a patient’s clinical manifestations. TCM practitioners must conduct a thorough analysis based on the patient’s overall symptoms and signs, exemplifyig the personalized nature of TCM disease management. However, due to the absence of objective measures, variability in treatment protocols may result in inconsistent clinical outcomes. Studies have demonstrated that tumor clinical stage correlates with objective indicators such as intestinal microbiota and T lymphocytes, revealing significant differences in metabolic characteristics[239,240,246]. These findings provide a foundation for establishing a predictive model for CRC progression and offer evidence supporting the scientific validity of TCM treatment principles.

In summary, TCM has unique advantages and great potential in treating CRC, particularly in its synergy with modern medicine and new drug development. While notable achievements have been made in this field, several challenges remain. Firstly, conducting high-quality multicenter prospective randomized controlled trials using blinded methods is difficult, especially for studies involving TCM compound formulations. Secondly, due to the extreme complexity of TCM components, screening active ingredients from single herbs and compound formulations, as well as understanding the synergistic effects among multiple components, remains a significant challenge in TCM development. Additionally, integrating the personalized treatment approaches characteristic of TCM, such as syndrome differentiation and treatment, with modern medicine and achieving clinical transformation poses another unresolved issue. As science and technology continue to advance and research methodologies are refined, particularly with the aid of cutting-edge technologies like artificial intelligence, these challenges are anticipated to be addressed. It is expected that in the near future, more safe and more effective TCM-based drugs and therapies will be developed, offering greater assistance and new hope to patients with CRC.