Cancer therapy-induced intestinal injury: Mechanisms, clinical manifestations, and management strategies

Abstract

As cancer treatment advances in recent years, people with cancer are living longer, but the side effects of these treatments on normal tissues remain a major challenge, particularly the intestines. Intestinal injury induced by chemotherapy, radiotherapy, targeted therapy, immunotherapy, and surgical intervention represents an important factor that limits the effectiveness of cancer treatment. The common symptoms are diarrhea, abdominal pain and malabsorption, which can substantially impair the patients’ quality of life and may lead to severe complications. At present, the clinical strategies for the prevention and treatment of therapy-induced intestinal injury are still relatively scarce. In this minireview, we focus on the mechanisms underlying cancer therapy-induced intestinal injury, including oxidative stress, inflammation, apoptosis, and gut microbiota imbalance, and discuss targeted therapeutic strategies aimed at reducing morbidity, improving patient outcomes, and fostering a better quality of life.

Key Words: Cancer therapy; Chemotherapy; Radiotherapy; Intestinal injury; Oxidative stress; Gut microbiota; Inflammation

Core Tip: Cancer therapy-induced intestinal injury is a relatively common, multifaceted side effect of chemotherapy, radiotherapy, targeted therapy, immunotherapy and surgical interventions. The underlying mechanisms include oxidative stress, inflammation, apoptosis and dysbiosis of the gut microbiota; all of them contribute to the disruption of epithelial integrity and intestinal function. This minireview synthesizes current mechanistic insights and therapeutic strategies, with a particular emphasis on microbiota modulation, targeted interventions, and emerging regenerative approaches. A comprehensive understanding of these processes is crucial for developing personalized treatments to prevent or mitigate intestinal injury, improve patient quality of life, and optimize cancer therapy outcomes.

INTRODUCTION

Over recent decades, cancer therapy has advanced considerably, with the emergence of treatments such as chemotherapy, radiotherapy, targeted therapy, immunotherapy, and surgery markedly improving survival rates and clinical outcomes for cancer patient[1]. Although these therapies can eliminate cancer cells, they often cause substantial damage to normal tissues, particularly the intestine, which represents a critical factor limiting therapeutic efficacy, quality of life, and long-term prognosis[2,3].

The intestine is an organ with good regenerative abilities that plays a central role in digestion, nutrient absorption, and immune regulation. Owing to the non-specific toxicity of anticancer therapies, it is particularly susceptible to treatment-related injury. The common clinical manifestations are diarrhoea, abdominal pain, malabsorption and weight loss (Table 1). The above symptoms may reduce patients’ quality of life and cause other systemic complications such as electrolyte disorders, dehydration or infection, and other life-threatening conditions. Intestinal injury also requires interrupting or stopping treatment prematurely, thereby reducing therapeutic efficacy and adversely affecting survival outcomes. The above issues will prolong hospitalisation and increase financial burden, imposing substantial physical and psychological stress on patients and their families[4].

Table 1 Incidence of intestinal injury (especially diarrhoea) caused by different kinds of cancer treatments.

Treatment type	Drug examples		Incidence of intestinal injury (especially diarrhea)	Ref.
Chemotherapy	Platinum-based agents	Cisplatin	< 1%	[8]
		Carboplatin	6%-10%
		Oxaliplatin	41%-56%
	Fluoropyrimidine	5-fluorouracil	13%-50%	[74]
		Capecitabine	30%-40%
	Irinotecan	Irinotecan (UGT1A1*1/*1)	Up to 87% experience delayed diarrhea; 40% severe	[17]
		Irinotecan (UGT1A1*28/*28)	A two-fold increase of risk of severe diarrhea
	Taxanes	Cabazitaxel	19%-47%	[75]
		Docetaxel	20%-40%
		Paclitaxel	17%-55%
Targeted therapy	EGFR-TKIs	Gefitinib	26%-52%, 1%-5%, grade 3-4	[76]
		Erlotinib	18%-57%, 3%-6%, grade 3-4	[77,78]
		Afatinib	87%-95%, 14%-22%, grade 3-4
		Cetuximab	13%-28%, 4%-28%, grade 3-4
	HER2-TKIs	Lapatinib	47%-75%, 3%-14%, grade 3-4	[79]
		Trastuzumab	2%-63%, 2%-6%, grade 3-4
		Pertuzumab	10%-67%, 5%-8%, grade 3-4
	VEGFR-TKIs	Bevacizumab	16%-20%, 2%-7%, grade 3-4	[58,80]
		Aflibercept	58%-69%, 13%-19%, grade 3-4	[81]
	Multi-target TKIs	Imatinib	20%-26%	[82]
		Sunitinib	44%-55%
		Sorafenib	43%-55%
Immunotherapy	PD-1/PD-L1 inhibitors	Nivolumab	8%-17%	[83,84]
		Pembrolizumab	2%-42%
		Atezolizumab	9%-11%
		Durvalumab	6%-50%
	CTLA-4 inhibitors	Ipilimumab	Diarrhea 27%-54%, colitis 8% to 22%, colon perforation 1%-1.5%	[70]
	LAG-3, TIM-3, and TIGIT	Relatlimab
Surgical treatment		N/A	30%-38%	[46]
Radiotherapy	Radiation	N/A	17%-60%	[69]

EGFR: Epidermal growth factor receptor; TKI: Tyrosine kinase inhibitor; VEGFR: Vascular endothelial growth factor receptor; HER2: Human epidermal growth factor receptor 2; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death ligand 1; CTLA-4: Cytotoxic T lymphocyte-associated protein 4; LAG-3: Lymphocyte activation gene 3; TIM-3: T-cell immunoglobulin and mucin-domain containing-3; TIGIT: T-cell immunoreceptor with Ig and ITIM domains.

Cancer therapy-related intestinal injuries can result not only in short-term symptoms but also in long-term consequences, including chronic intestinal dysfunction, persistent malnutrition, and disruptions in the gut microbiota. These issues will prevent recovery and increase other toxicities of the treatment. Although research on intestinal injury has expanded in recent years, most of the clinical management is still supportive, and few effective preventive or targeted therapeutic strategies have been developed. Therefore, additional research needs to be conducted on cancer therapy-induced intestinal injury[5].

In this review, we provide a systematic summary of the effects of chemotherapy, radiotherapy, targeted therapy, immunotherapy, and surgical interventions on intestinal health. We also discuss the underlying mechanisms of therapy-induced intestinal injury and corresponding management strategies, as well as the current status of research, ongoing challenges, and potential approaches to optimize treatment (Figure 1). This minireview aims to inform researchers and clinicians, facilitating the development of more precise and effective preventive and therapeutic strategies to optimise cancer care, reduce patient burden, and enhance long-term outcomes.

Figure 1 Mechanisms and treatment strategies for cancer therapy-induced intestinal injury. Left: Principal mechanisms underlying intestinal injury induced by chemotherapy, radiotherapy, targeted therapy, immunotherapy, and surgical treatment include reactive oxygen species generation, gut microbiota dysbiosis, epithelial barrier dysfunction, ischaemia, immune cell infiltration, and short-chain fatty acid reduction. Right: Key treatment strategies include symptomatic supportive care, mechanism-targeted interventions, and modulation of gut microbiota to restore intestinal homeostasis. TNF-α: Tumour necrosis factor-alpha; IL: Interleukin; ROS: Reactive oxygen species; EGFR: Epidermal growth factor receptor; TKI: Tyrosine kinase inhibitor; VEGFR: Vascular endothelial growth factor receptor; SCFA: Short-chain fatty acid; IVIG: Intravenous immunoglobulin; FMT: Faecal microbiota transplantation. Created using BioRender.

CHEMOTHERAPY-INDUCED INTESTINAL INJURY

Chemotherapy-induced intestinal injury is a common adverse effect associated with multiple chemotherapeutic agents and radiotherapy regimens[6]. Clinical manifestations include diarrhoea, abdominal pain, weight loss, constipation, and mucosal ulceration[7]. The prevalence and severity of these symptoms vary according to the type and dose of chemotherapy, as well as individual patient characteristics.

Chemotherapy remains a principal modality in cancer treatment; however, it non-selectively targets rapidly proliferating cells, resulting in damage to the intestinal epithelium and marked toxicity. Approximately 40% of patients receiving standard-dose chemotherapy develop intestinal injury, with substantially higher incidence reported at increased doses. Estimates indicate that 60%-100% of patients receiving high-dose chemotherapy experience intestinal injury[7].

Platinum-based drugs

Platinum-based agents, including cisplatin, carboplatin, and oxaliplatin, exert anticancer effects through DNA adduct formation, thereby inhibiting DNA replication and transcription and inducing tumour cell death. Cisplatin, introduced into clinical use in 1978, is widely employed in the treatment of cancers of the testis, bladder, lung, ovary, and head and neck. However, its considerable nephrotoxicity has led to the development of carboplatin, a structurally related agent with reduced toxicity[8]. Oxaliplatin is a third-generation platinum-based chemotherapeutic drug that is particularly effective in treating colorectal cancer. It is commonly used in combination with 5-fluorouracil (5-FU) and leucovorin as first-line treatment[9]. Despite the effectiveness of platinum-based drugs, severe intestinal injury remains a common side effect[10]. Approximately 70%-80% of chemotherapy patients experience nausea or vomiting, and approximately 67% develop diarrhoea.

Platinum-based drugs enhance the release of serotonin (5-HT) from enterochromaffin cells into the intestine. 5-HT, an important neurotransmitter, acts via the 5-HT3 receptor, which is a major target in diarrhoea onset. Activation of the 5-HT3 receptor stimulates the release of vasoactive intestinal peptides through neural mechanisms. Vasoactive intestinal peptides increase fluid secretion in the intestines and promotes intestinal motility, exacerbating diarrhoea symptoms[10].

Taxane-based drugs

Taxane-based agents, including cabazitaxel, paclitaxel, and docetaxel, are microtubule-stabilising agents widely used in the treatment of breast, ovarian, and non-small cell lung cancer (NSCLC). These agents stabilise microtubules and inhibit depolymerisation, thereby suppressing mitosis and cellular proliferation. However, this effect is not tumour-specific and also impairs normal intestinal epithelial cell function. Given the high regenerative capacity of intestinal epithelial cells, disruption of microtubule dynamics adversely affects cell division and mucosal repair. When taxane-based drugs interfere with the dynamic nature of microtubules in intestinal epithelial cells, they inhibit their division and repair[11]. This leads to impaired intestinal barrier function, causing the death of intestinal epithelial cells, and resulting in mucosal damage, which further exacerbates symptoms such as diarrhoea, abdominal pain, and intestinal perforation.

Fluoropyrimidine

Fluoropyrimidines, including 5-FU and its oral prodrug capecitabine, are widely used antimetabolite drugs in cancer treatment. 5-FU is a pyrimidine analogue that targets thymidylate synthase, an enzyme required for DNA synthesis and cell replication. By inhibiting thymidylate synthase, 5-FU disrupts the production of thymidine, which is a necessary precursor for DNA synthesis. This disruption leads to double-stranded breaks in both DNA and RNA, followed by cell cycle arrest, and apoptosis, thereby suppressing cancer cell proliferation. In addition, 5-FU interferes with DNA repair and elongation, which further enhances its cytotoxicity[12]. Capecitabine is an oral prodrug that undergoes enzymatic conversion to active 5-FU. This conversion process is relatively selective, concentrating the drug’s effects mainly in cancer cells while partially sparing normal tissues. However, the cytotoxic activity of capecitabine is not restricted to malignant cells, resulting in off target effects, particularly in rapidly dividing intestinal epithelial cells. Common side effects include diarrhoea and intestinal mucositis[13].

Dihydropyrimidine dehydrogenase (DPD) plays an important role in 5-FU-induced intestinal injury. Encoded by the DPD (DPYD) gene, DPD serves as the primary enzyme that metabolises 5-FU into nontoxic metabolites. However, individual variations in DPD activity directly affect patient tolerance to 5-FU and its associated side effects, particularly intestinal injury. Patients with low DPD activity have reduced capacity to metabolise 5-FU, leading to drug accumulation and heightened injury, and are more prone to intestinal symptoms such as inflammation, diarrhoea, and nausea during 5-FU treatment[14]. This buildup prolongs 5-FU retention in the intestinal tract, exacerbating its direct injury to intestinal epithelial cells and resulting in mucosal damage. Variations in the DPD gene that affect enzyme activity are key factors affecting patient tolerance to 5-FU. Patients with DPYD gene mutations are at a higher risk of 5-FU-related injuries, making DPD gene screening an important measure for personalised treatment planning to reduce chemotherapy-associated intestinal injuries[15].

Irinotecan

Irinotecan is a broad-spectrum anticancer agent, which is commonly used against colorectal cancer, lung cancer, and other solid tumours[16]. The drug acts by inhibiting topoisomerase I, an enzyme essential for DNA replication. Irinoctan binds to DNA to form a DNA-enzyme complex; then, replication produces a damaging protein-DNA adduct that triggers apoptosis. However, irinotecan has relatively severe and unpredictable dose-limiting toxicities, such as diarrhoea, so it is not often used[17].

According to the Common Terminology Criteria of Adverse Events released by the National Cancer Institute, a large number of patients with irinotecan-based chemotherapy experience delayed diarrhoea; about 87% of them meet the criteria for delayed diarrhoea, and approximately 40% of these cases are serious diarrhoea (grades 3 or 4). Generally speaking, two types of irinotecan-associated diarrhoea are classified as early-onset and late-onset. Early-onset diarrhoea generally occurs within 24 hours after drug administration; delayed diarrhoea is relatively more severe and has a long delay in onset, it is typically not cholinergically mediated but likely involves multiple mechanisms, primarily related to irinotecan metabolism and elimination. This makes the clinical management of delayed diarrhoea much more complex[17]. Diarrhoea in response to irinotecan is caused by an increased release of the active metabolite SN-38 in the intestine. SN-38 is converted in the liver into a less toxic form, SN-38G, which is excreted in the intestine. However, β-glucuronidase from gut microbiota can reactivate SN-38G into SN-38, leading to intestinal epithelial damage, dysbiosis, and inflammation, ultimately causing delayed diarrhoea[18]. Genetic factors significantly influence the risk of diarrhoea, particularly UDP glucuronosyltransferase family 1 member A1 (UGT1A1) gene polymorphisms (such as UGT1A1*28), which reduce UGT1A1 enzyme activity, leading to an accumulation of SN-38 and increased risk of diarrhoea.

Common mechanisms of intestinal injury

Oxidative stress: Oxidative stress represents a central mechanism underlying chemotherapy-induced intestinal injury[4]. Reactive oxygen species (ROS) interact with lipids and proteins in cellular membranes, particularly within mitochondrial structures, thereby disrupting membrane integrity and function[19]. ROS-induced mitochondrial dysfunction impairs ATP production and disrupts intracellular calcium homeostasis, ultimately triggering apoptosis. Platinum-based agents, for example, generate ROS that damage mitochondrial membranes and impair cellular function[20]. In addition, ROS-mediated DNA strand breaks disrupt gene expression and inhibit epithelial regeneration, thereby exacerbating mucosal injury (Figure 2).

Figure 2 Mechanisms of chemotherapy-induced intestinal injury: Oxidative stress and apoptosis. Left: Chemotherapeutic agents induce oxidative stress through excessive reactive oxygen species production, resulting in mitochondrial dysfunction, disruption of calcium ion homeostasis, and DNA damage. Right: Chemotherapeutic agents activate apoptotic pathways via Bax-mediated mitochondrial outer membrane permeabilisation, cytochrome c release, and cell cycle arrest, leading to activation of the caspase cascade and apoptosis of intestinal epithelial cells. ROS: Reactive oxygen species. Created using BioRender.

Inflammatory responses: Oxidative stress not only causes direct cellular damage but also activates a range of inflammatory cytokines and chemokines, which in turn recruit and infiltrate inflammatory cells, driving the inflammatory response in the intestine[21]. Studies have shown that platinum-based drugs, such as cisplatin, activate the nuclear factor kappa-B and tumour necrosis factor-alpha (TNF-α) signalling pathways, further aggravating intestinal inflammation. Similarly, 5-FU and its metabolites also induce ROS generation, which activates nuclear factor kappa-B signalling. This, in turn, promotes the release of proinflammatory cytokines like interleukin (IL)-1β, IL-6, and TNF-α, which drive intestinal inflammation and exacerbate mucosal damage[21]. These inflammatory responses not only worsen intestinal water absorption dysfunction, but also increase intestinal permeability, ultimately leading to diarrhoea.

Apoptosis: A key mechanism for chemotherapy-induced intestinal injury is apoptosis. Platinum compounds, 5-FU and taxanes are typical agents that can increase the expression of pro-apoptotic proteins such as Bax, thus inducing mitochondrial outer membrane permeabilization, releasing cytochrome c, or inhibiting microtubule depolymerisation and cell cycle progression. These pathways finally trigger caspase cascades and thus cause apoptosis in intestinal epithelial cells[22]. Apoptosis-mediated damage to the intestinal mucosa impairs water absorption and increases intestinal permeability, resulting in diarrhoea and related symptoms (Figure 2).

Gut microbiota: Chemotherapeutic drugs change the composition of gut microbiota and cause damage to the intestine; 5-FU decreases beneficial bacteria such as Lactobacillus and increases pathogenic taxa, including Enterococcus and Clostridium[23]. Taxanes, platinum-based agents and irinotecan can also reduce microbial diversity. This dysbiosis disrupts normal barrier function and promotes inflammation.

Mechanistic interactions in intestinal injury: These mechanisms are highly interconnected. Oxidative stress often acts as an upstream trigger, with excessive ROS production inducing mitochondrial dysfunction, DNA damage, and cellular stress, followed by activation of inflammatory signalling pathways[24]. The released pro-inflammatory cytokines will also damage the epithelial cells and trigger apoptosis, leading to bacterial translocation and microbial dysbiosis[25]. Altered composition of the gut microbiota and associated metabolite imbalance further exacerbate oxidative stress and inflammation, establishing a self-reinforcing pathogenic cycle that amplifies the condition[26].

TARGETED THERAPY-INDUCED INTESTINAL INJURY

Targeted therapy refers to specific oncological treatments aimed at inhibiting the growth of tumour by blocking certain pathways[27]. Therapy will be effective for some patients with relevant molecular targets. However, there is also damage to the intestine; thus, life quality will be reduced and treatment will be interrupted.

Anti-epidermal growth factor receptor

Epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase family, regulates cell proliferation, differentiation, and survival. Therapeutic strategies targeting EGFR include tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. EGFR-TKIs inhibit receptor phosphorylation and downstream signalling, thereby suppressing tumour cell proliferation and survival. However, EGFR is also expressed in normal intestinal epithelial cells, where it is essential for mucosal homeostasis. Inhibition of EGFR disrupts epithelial regeneration and barrier integrity, leading to diarrhoea and other intestinal complications. These effects are partly mediated by impaired epithelial repair and altered chloride secretion. In vitro studies demonstrate that lapatinib inhibits the proliferation of normal intestinal epithelial cells and induces late-stage apoptosis[28].

EGFR-TKIs promote the abnormal secretion of chloride ions and disrupt fluid balance in the intestine. Under normal conditions, EGFR activation inhibits calcium-dependent chloride secretion, maintaining the balance of chloride ions in the intestine. However, when EGFR is inhibited, this mechanism is disrupted, leading to the abnormal accumulation of chloride ions and the subsequent influx of water into the intestinal lumen, resulting in diarrhoea[29].

Anti-vascular endothelial growth factor receptor

Vascular endothelial growth factor receptor (VEGFR) is central to tumour angiogenesis, facilitating the formation of new blood vessels that supply nutrients and oxygen to tumours[30]. Inhibition of the VEGF/VEGFR signalling pathway reduces tumour vascularisation and suppresses tumour growth and metastasis. Bevacizumab, a monoclonal antibody targeting VEGF, is widely used in patients with colorectal cancer, NSCLC, and other malignancies. Additionally, VEGFR-TKIs, such as aflibercept, inhibit angiogenesis by targeting VEGFR signalling pathways.

VEGFR-TKIs exert their effects by inhibiting the VEGF and VEGFR signalling pathways, and reduce blood supply not only to tumours but also to normal tissues, including the intestine. This can lead to intestinal mucosal ischaemia, which is a key mechanism underlying VEGFR-TKI-induced diarrhoea. Patients treated with bevacizumab exhibit changes in the intestinal mucosa similar to that in patients with ischaemic colitis.

Anti-human epidermal growth factor receptor 2

Human epidermal growth factor receptor 2 (HER2) is an important target in cancer treatment, particularly HER2-positive breast and gastric cancers[31]. Currently, anti-HER2 therapies, including trastuzumab, pertuzumab, and lapatinib, are standard treatments for HER2-positive breast cancer. These drugs target HER2 receptors, either by blocking their extracellular domains or by inhibiting intracellular signalling[32].

Although HER2 inhibitors effectively target HER2-positive tumours, they may disrupt intestinal homeostasis by impairing the regeneration and repair of intestinal epithelial cells, leading to diarrhoea. The mechanism of intestinal injury induced by HER2-targeted therapies is similar to that induced by EGFR inhibitors because both reduce the proliferation and repair capacity of intestinal epithelial cells.

Multi-target TKIs

In addition to EGFR, VEGFR, and HER2, other receptors, such as anaplastic lymphoma kinase, B-Raf proto-oncogene, ret proto-oncogene, and MET proto-oncogene, are targeted by multi-target TKIs. These therapies are used for treating various cancers, including NSCLC, melanoma, and thyroid cancer[33]. Multi-target TKIs, such as imatinib, sunitinib, and sorafenib, simultaneously inhibit several receptor tyrosine kinases, offering a broad therapeutic benefit, and are used to treat various cancers, including NSCLC, melanoma, and thyroid cancer. However, the multi-target nature of these drugs often leads to a higher incidence of intestinal injuries. One of the primary mechanisms of intestinal injuries involves the inhibition of c-KIT, a receptor tyrosine kinase that plays a role in regulating intestinal motility. Inhibition of c-KIT by multi-target TKIs such as imatinib can lead to intestinal motility disorders, resulting in diarrhoea[33].

Common mechanisms

Despite the differences in specific targets of these therapies, a common feature of all targeted therapies is the activation of local inflammatory responses, changes in barrier function, and alterations in the gut microbiota, all of which contribute to intestinal injury. A large proportion of inflammatory response and chloride secretion for fluid regulation in the gut are carried out by the gut microbiota. Studies have shown that VEGFR-TKIs may reduce the abundance of beneficial bacteria such as Bifidobacterium, while diarrhoea patients exhibit higher levels of Bacteroides species and lower levels of Prevotella species, suggesting a correlation between changes in the microbiome and the development of diarrhoea[34].

IMMUNOTHERAPY-INDUCED INTESTINAL INJURY

Tumour immunotherapy represents a major advance in cancer treatment by enhancing immune-mediated tumour eradication and overcoming immune tolerance. Immune checkpoint inhibitors restore antitumour immunity by blocking inhibitory signalling pathways, thereby activating T cells[35]. However, these agents may induce immune-related intestinal inflammation, resulting in intestinal injury.

Programmed cell death protein 1/ligand 1

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor expressed on activated T cells, B cells, and natural killer (NK) cells[36]. Binding of PD-1 to its ligand, programmed cell death ligand 1 (PD-L1), suppresses T cell activation and effector function, thereby preventing excessive immune responses. Within the tumour microenvironment, PD-1/PD-L1 signalling contributes to immune evasion. PD-L1 is frequently upregulated on tumour cells and tumour-associated immune cells, including macrophages and dendritic cells, via interferon-γ signalling, leading to suppression of antitumour T cell activity. PD-1 inhibitors block this interaction, thereby restoring T cell function and enhancing tumour cell clearance.

PD-1/PD-L1 inhibitors induce intestinal injury by hyperactivating CD8+ cytotoxic T cells[37]. CD8+ T cells produce cytotoxic factors that damage intestinal epithelial cells and release pro-inflammatory cytokines, such as interferon-γ and TNF-α, leading to impaired mucosal barrier function, gut microbiota dysbiosis, and exacerbation of intestinal inflammation[38].

Cytotoxic T lymphocyte-associated protein 4

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is an inhibitory immune checkpoint that binds to CD80/CD86 in a competing manner and thereby prevents CD28-mediated co-stimulation of T cells. CTLA-4 is a natural negative regulator of T cell activation, maintaining immune tolerance and preventing autoimmunity. Elevated CTLA-4 expression in the tumour microenvironment excessively suppresses T cell activity, reducing the immune system’s ability to attack tumor cells and facilitating tumor immune evasion[39].

CTLA-4 inhibitors prevent CTLA-4 from binding to CD80/CD86, making T cells more readily activated and promoting antitumour immunity. CTLA-4 is also highly expressed on CD25+ CD4+ regulatory T cells (Tregs), where it enhances immunosuppressive function[40]. CTLA-4 inhibitors alter the number and function of Tregs, promoting the release of pro-inflammatory cytokines, such as IL-2 and TNF-α, to worsen intestinal inflammation[37].

Lymphocyte activation gene 3, T-cell immunoglobulin and mucin-domain containing-3, and T-cell immunoreceptor with Ig and ITIM domains

Lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) are well-known immune checkpoint molecules that regulate the activity of T cells, enhance immunosuppressive functions, and help maintain immune homeostasis in the intestine[41]. Together, these molecules help the tumour evade immune surveillance[42].

LAG-3 binds to major histocompatibility complex-II molecules, suppresses the activation of T cells and improves the function of Tregs[43]. TIM-3 is expressed in many kinds of immune cells, such as T cells, NK cells and dendritic cells. It interacts with ligands such as galectin-9 to suppress T cell activity[44]. TIGIT binds to ligands CD155 and CD112, competing with the co-stimulatory molecule CD226, and thus suppresses the activity of effector T cells and NK cells[45]. Although these immune checkpoints have been widely studied in tumour immunotherapy, their functions in intestinal injury are still unclear. Research has shown that LAG-3, TIM-3 and TIGIT exacerbate inflammatory intestinal injury by disrupting the balance of immune cells and interfering with the gut microbiota.

SURGICAL TREATMENT-INDUCED INTESTINAL INJURY: FOCUS ON DIVERSION COLITIS

Diversion colitis (DC) is a common intestinal complication following tumour surgery, particularly in patients undergoing stoma creation or bowel diversion surgeries for colorectal cancer or other pelvic malignancies[46]. Surgical alteration of bowel continuity results in the loss of normal faecal flow in the distal diverted bowel segment, leading to a series of specific pathological changes. This condition manifests as chronic inflammation in the diverted bowel segment, with symptoms such as mucus discharge, rectal bleeding, tenesmus, and abdominal pain. Nearly all diverted bowel segments exhibit endoscopic evidence of inflammation within 3-36 months after surgery, although only approximately 30% of patients show significant symptoms. DC will continuously harm the intestine and may cause serious problems such as intestinal strictures and fistula formation.

Although the exact pathogenesis for DC are not yet known, the core mechanisms are thought to involve dysbiosis, short-chain fatty acid (SCFA) deficiency, and relative ischaemia. Under normal circumstances, the gut microbiota is able to produce SCFAs such as butyrate through fermentation of dietary fibres to provide an energy source for intestinal epithelial cells and maintain the health of the intestinal lining[47]. However, in the diverted bowel segment, there is an interruption of faecal flow; thus, carbohydrate-fermenting bacteria are less active and their metabolic functions have declined, resulting in a reduction of SCFA levels. This further disrupts the mucosal barrier function and triggers inflammatory responses.

DC is also linked to local ischaemia. SCFA deficiency may increase pelvic arterial tone and cause relative ischaemia in the colorectal mucosa and intestinal wall[48]. This ischaemic state further damages the intestinal barrier function. The immune system plays a crucial role in the development of DC. Prolonged lack of normal antigenic stimulation disrupts local immune homeostasis, leading to an increase in inflammatory cytokines, such as TNF-α and IL-6, and thus creating a pathological environment of chronic inflammation.

A DC anastomosis is generally a surgical connection of the bowel that reverses a stoma. The normalisation of faecal flow, restoration of a balanced gut microbial community, and increased SCFA production lead to significant symptom improvement. Pharmacological treatment may be used for patients who cannot undergo stoma reversal, such as SCFA enemas[49], topical 5-aminosalicylic acid[50], or corticosteroids. SCFA enemas, such as butyrate enemas, have shown efficacy in managing symptoms and promoting the healing of damaged mucous membranes.

In conclusion, DC is a particular type of intestinal injury that occurs after tumour surgery, and it has a multi-factorial pathogenesis involving dysbiosis, metabolic disorders and immune imbalance. Stoma reversal can be adopted to solve this problem, but more research will be conducted in the future to develop localised treatments for patients who are not eligible for surgery.

RADIOTHERAPY-INDUCED INTESTINAL INJURY

Pelvic radiotherapy is a principal modality in the treatment of malignancies, including cancers of the cervix, prostate, and rectum. With the development of radiotherapy technology in recent years, many new kinds of high-precision radiation therapies have appeared, such as intensity-modulated radiotherapy, image-guided radiotherapy, and proton therapy, which have improved targeting accuracy and dose distribution, thereby reducing exposure of normal tissues. Although the way to deliver the treatment has been improved, up to 50% of patients undergoing abdominal and pelvic radiotherapy have suffered from intestinal injury, and about 10% have had serious long-term complications. A high number of cases indicates intestinal injury as a major adverse effect and may be a reason for limited therapeutic efficacy.

After radiotherapy, acute intestinal injury usually occurs a few days or weeks later as a result of direct and indirect injury to the rapidly proliferating epithelial cells in the intestinal crypts by radiation. Ionising radiation causes damage to DNA and increases the production of ROS and reactive nitrogen species; therefore, the crypt stem cells and their microenvironment are damaged rapidly, leading to rapid impairment of the intestinal barrier[51]. Radiation also reduces the expression of tight junction proteins, such as claudins and occludins, decreases the number of goblet cells, and thus thins the mucus layer and increases the vulnerability of the lamina propria to luminal invasion. This will cause the bacteria to spread throughout the blood vessels in the body, and then these bacteria will cause harm to all parts of the body by releasing toxic substances.

Chronic intestinal injury occurs several months or years after radiation therapy (RT) completion and is associated with the following mechanisms: Vascular damage, chronic inflammation, fibrosis and microbial dysbiosis[52]. Radiation-induced apoptosis of vascular endothelial cells and microvascular occlusion result in localised ischaemia and thus in the progression of fibrosis. Transforming growth factor-β1 and other profibrotic factors lead to the overproduction of extracellular matrix and thus cause hardening and narrowing of the intestinal wall and lumen. Radiation can also reduce the release of anti-inflammatory cytokines such as IL-10 and increase the expression of pro-inflammatory cytokines, including IL-6 and TNF-α, thus extending injury to the mucosa.

RT-induced intestinal injury refers to cell injury and other complex relationships among hosts and gut microbiota. Research has shown that radiation causes severe dysbiosis of the gut microbiota, there is a reduction in beneficial bacteria such as Bifidobacteria and Lactobacilli, and an increase in opportunistic pathogens such as Proteobacteria and Clostridia. Altered gut microbiota have also hindered epithelial repair after RT, and a significant reduction in SCFAs, such as butyrate, has occurred. Butyrate is a source of energy for the intestinal epithelial cells, and its deficiency significantly weakens barrier repair and anti-inflammatory functions[53].

TREATMENT

Cancer therapy-induced intestinal injury involves multifactorial pathological processes. Management strategies should prioritise both symptomatic relief and targeted intervention of underlying mechanisms, with individualised approaches to optimise short- and long-term outcomes. Current management includes supportive care, immune modulation, targeted therapies, and emerging treatment strategies. These approaches act in combination to provide a comprehensive framework for the management of cancer therapy-induced intestinal injury[54].

Symptomatic treatment

Symptomatic treatment plays an important role in managing cancer therapy-induced intestinal injury, particularly for alleviating acute symptoms. For patients with mild-to-moderate diarrhoea, loperamide is commonly used. It suppresses intestinal smooth muscle activity and provides rapid symptom relief. For severe or persistent diarrhoea, such as late-onset diarrhoea caused by irinotecan, adding octreotide has been shown to be effective. Octreotide reduces intestinal secretions and regulates electrolyte balance, further alleviating symptoms.

Immunothreapy-induced intestinal injuries require more precise symptomatic interventions[55]. In such cases, corticosteroids are used as first-line therapy. They suppress T-cell activation and reduce inflammatory cytokine release, leading to rapid symptom relief[56]. For steroid-refractory cases or those requiring stronger immunosuppression, commonly used treatment options include TNF-α antagonists, intravenous immunoglobulin, mycophenolate mofetil, and methotrexate[57,58]. Additionally, timely electrolyte supplementation, maintaining hydration, and providing intravenous nutritional support are also critical measures to prevent further deterioration of symptoms.

Targeted mechanism-based interventions

When specific molecular and pathological mechanisms have been identified, targeted interventions become particularly important in the management of cancer therapy-induced intestinal injury. Two major pathological drivers of intestinal injury caused by radiotherapy and chemotherapy are oxidative stress and inflammatory responses. Antioxidants such as glutathione and alpha-lipoic acid reduce the production of ROS, protect intestinal epithelial cells from oxidative damage, and show promising effects in managing chemotherapy-induced intestinal injury[4].

Moreover, excessive activation of inflammatory mediators is another key mechanism in cancer therapy-induced intestinal injury[59]. TNF-α inhibitors, such as infliximab, block TNF-α-mediated inflammatory cascades, significantly reducing intestinal inflammation and promoting repair[60]. Similarly, IL-6 inhibitors have shown potential in preclinical studies to alleviate intestinal damage[61]. For crypt stem cell apoptosis caused by radiotherapy and chemotherapy, glucagon-like peptide-2 has been widely studied, with results demonstrating its ability to promote intestinal mucosal regeneration and enhance barrier function, providing a novel therapeutic option for intestinal injury[62].

Modulation of gut microbiota

Disruption of the gut microbiota by cancer treatment frequently leads to intestinal injury and can worsen the extent of this damage. Therefore, rebalancing the microbial community is required in the treatment. Probiotics such as Bifidobacteria and Lactobacilli improve the stability of gut microbial populations, reduce the proliferation of pathogenic microbes and alleviate local inflammation. The above agents have been applied in the treatment of chemotherapy- and immunotherapy-induced intestinal injury to some extent[63].

Patients with severe dysbiosis have shown good results after faecal microbiota transplantation[64]. Faecal microbiota transplantation may restore microbial balance, reduce inflammation, and promote mucosal repair. Adding SCFAs such as butyrate can strengthen intestinal barrier function and provide anti-inflammatory benefits, supporting the recovery of intestinal function[65].

Although the traditional treatments for intestinal injuries are still widely in use, new therapies have gradually started to attract the attention of people in recent years. Mesenchymal stem cells are representative examples in repairing radiation-induced intestinal injury by reducing inflammation and promoting regeneration. Gene editing and nanoparticle drug delivery are relatively new methods that may help to address some of the problems mentioned earlier[66-68] (Table 2).

Table 2 Therapeutic drugs/measures for intestinal injury caused by different kinds of cancer treatments.

Treatment category	Drugs/measures	Mechanism	Clinical evidence level	Ref.
Symptomatic treatment	Loperamide, octreotide	Relieves symptoms by regulating intestinal activity and secretions	2	[67]
Immune modulation and immunotherapy	Corticosteroids, TNF-α antagonists, intravenous immunoglobulin, mycophenolate mofetil, methotrexate	Suppresses immune activation and reduces inflammation-related damage	2	[56-58]
Antioxidant and anti-inflammatory treatment	Glutathione, alpha-lipoic acid, TNF-α inhibitors, interleukin-6 inhibitors	Reduces oxidative stress and inflammation to protect intestinal cells	2-3	[4,60,61,68]
Stem cell and gut microbiota modulation	Glucagon-like peptide-2, probiotics, fecal microbiota transplantation, short-chain fatty acids	Enhances epithelial cell repair and restores gut microbiota balance	2-3	[62-65]
Emerging therapies	Mesenchymal stem cells, gene editing, nanoparticle drug delivery	Stimulates regeneration and promotes recovery through advanced techniques	4-5	[66]

Clinical evidence levels (1-5) in this table are assigned according to the 2011 Oxford Levels of Evidence (Centre for Evidence-Based Medicine, University of Oxford). Level 1 represents high-quality evidence derived from systematic reviews or randomized controlled trials; level 2 represents moderate-quality evidence from individual randomized controlled trials, cohort studies, or observational studies with dramatic effect; level 3 represents evidence from non-randomized controlled cohort or case-control studies; level 4 represents evidence from case series, poor-quality cohort/case-control studies, or historically controlled studies; level 5 represents expert opinion or mechanism-based reasoning. These levels reflect the reliability of clinical evidence supporting each intervention. TNF-α: Tumour necrosis factor-alpha.

DISCUSSION

Cancer therapy-induced intestinal injury has still occurred in patients at a higher rate, and both their quality of life and adherence to treatment have been adversely affected. This minireview systematically evaluated the mechanisms, clinical manifestations, and management strategies associated with intestinal injury across major cancer treatment modalities, including chemotherapy, radiotherapy, targeted therapy, immunotherapy, and surgical intervention. Notably, these modalities differ considerably in both the severity and characteristics of intestinal injury.

Distinct patterns of intestinal injury are observed across treatment modalities. Chemotherapy is generally linked to serious adverse effects, such as diarrhoea and mucosal inflammation, at a relatively high rate. Intestinal injury has occurred in 60%-100% of patients receiving high-dose chemotherapy[7,17]. Therefore, most of the high risk of intestinal injury still stems from chemotherapy.

Radiotherapy only causes acute epithelial damage and progressive, often irreversible structural alterations. Radiotherapy-induced intestinal injury involves vascular damage, ischaemia, fibrosis, and long-term functional impairment[52,69]. Although acute symptoms are common, the typical problems caused by radiotherapy are generally chronic in nature, may persist for several months or even years, and substantially impair patients’ quality of life.

Immunotherapy, particularly immune checkpoint inhibitors, have different types of injury. Diarrhoea is relatively rare after immunotherapy, but intestinal injury caused by immunotherapy may be more serious[35,37]. CTLA-4 inhibitors, such as ipilimumab, are associated with an increased risk of colitis, and severe mucosal inflammation or intestinal perforation may occur in advanced cases[70].

Overall, chemotherapy is the main cause of intestinal injury, and the symptoms mainly include diarrhoea; radiotherapy and immunotherapy are more closely associated with structural and immune-mediated injury, respectively. Despite modality-specific differences, disruption of gut microbiota represents a shared underlying pathway linking these treatments to epithelial injury and inflammation.

Studies show that cancer treatment has changed the composition and function of gut microbiota[71]. Although they have different mechanisms of action, chemotherapy, radiotherapy, immunotherapy, targeted therapy and surgery all involve disruption of microbial homeostasis. It generally has a lower microbial diversity, a reduction in beneficial commensal bacteria, and an increase in potentially pathogenic groups.

Chemotherapy and radiotherapy consistently disrupt microbial homeostasis; thus, beneficial species such as Bifidobacterium and Lactobacillus decline, and pathogenic Proteobacteria and Clostridium increase. Microbiota changes due to radiotherapy and surgery often lead to a reduction of key metabolites, such as SCFAs[72]. Immunotherapy and targeted therapies also alter the gut microbiota, but the degree and pattern of change vary among different agents[73]. The above changes have damaged the epithelial barrier, increased intestinal permeability and promoted inflammation of the mucosa, and thus caused intestinal injury. Taken together, the above results support gut microbiota as a common mechanistic pathway and a possible therapeutic target for cancer therapy-induced intestinal injury.

CONCLUSION

Cancer therapy-induced intestinal injury is a multifactorial and prevalent complication that substantially impairs patient quality of life and may limit effectiveness of oncological treatment. The present management strategies are mainly in the form of symptomatic relief, which provides partial relief but does not adequately address underlying mechanisms. Future research should focus on elucidating precise molecular and microbial pathways and developing personalised therapeutic strategies to prevent and mitigate intestinal injury. A deeper understanding of the mechanism will help to address the present treatment deficiencies, enhance treatment adherence, and optimise long-term oncological outcomes.