Unveiling the anticancer potential of SGLT-2 inhibitors: mechanisms and prospects in clinical oncology—a narrative review

Abstract

In recent years, cancer has become more prevalent among younger populations, increasing the burden on public health and the economy. Current cancer treatments are often costly and have long trial periods. Sodium-glucose cotransporter-2 inhibitors (SGLT-2is), including dapagliflozin and canagliflozin, were originally developed for blood glucose control, but have shown promise in anticancer applications. These inhibitors work by inhibiting glucose uptake in tumor cells, thus limiting the energy supply needed for tumor growth. For instance, in lung and hepatocellular cancers, SGLT-2is have been demonstrated to reduce tumor volume and suppress metastasis by modulating key signaling pathways, such as AMPK/mTOR and HIF-1α. Additionally, their ability to enhance the efficacy of chemotherapy and immunotherapy further underscores their potential in cancer treatment. Numerous studies have been conducted on this topic. Diabetes mellitus (DM) is increasingly affecting younger populations and overlaps significantly with cancer. DM patients face higher cancer risks, particularly for liver, colorectal, and pancreatic cancers, with studies indicating up to a 20% increased risk. This highlights the need to consider both conditions in treatment strategies and understand the mechanisms linking DM and cancer to improve outcomes. This study explores the relationship between SGLT-2is and cancer, focusing on their mechanisms in various tumor types and their synergistic effects in combination with other therapies. In the current study, we determined the relationship between SGLT-2is and cancer, and elaborated on the role and mechanisms of SGLT-2is in tumors at different primary sites. In addition, we introduced the anti-tumor effects of SGLT-2is in combination with other means and the underlying mechanisms. From the single-operator to combined-operator level, we reveal the prospects of SGLT-2is in clinical oncology and the future outlook.

Introduction

According to the 2024 Cancer Statistics Report, over 2 million new cancer cases and 600,000 cancer-related deaths are expected in the United States by 2024 [1]. Notably, cancer incidence among young adults (20–40 years old) in China has significantly increased over the past two decades [2]. Breast, lung, and colorectal cancers remain the most common worldwide [3]. With the aging population, cancer-related deaths are expected to continue rising, presenting a significant public health challenge.

As the second leading cause of death globally after cardiovascular disease, tumors pose a persistent challenge to clinical treatment [4]. Current therapies, including radiotherapy, chemotherapy, surgery, immunotherapy, and targeted therapy, are associated with various limitations such as poor selectivity, high costs, and significant side effects [5, 6]. Targeted therapy relies on specific molecular targets, such as epidermal growth factor receptor (EGFR), which has been shown to play a critical role in the development and progression of both breast and non-small cell lung cancers [7]. However, such therapies are not universally effective, particularly in tumors lacking these targets or those exhibiting resistance. Moreover, signaling pathways involving long-chain non-coding RNAs and reactive oxygen species (ROS) have emerged as important contributors to tumor biology and therapeutic resistance, further complicating treatment design [8]. Therefore, there is an urgent need for new therapeutic approaches that are both targeted and cost-effective. Sodium-glucose cotransporter-2 inhibitors (SGLT-2is), originally developed for the management of DM, have shown promise as potential anticancer agents [9]. Recent studies indicate that SGLT-2is can inhibit tumor growth by limiting glucose uptake in tumor cells, a key source of energy for cancer progression [10].

Unlike conventional therapies, which indiscriminately damage both tumor and normal cells, SGLT-2 inhibitors (SGLT-2is) work by selectively targeting glucose uptake in tumor cells, limiting their energy supply without affecting healthy tissues. This makes SGLT-2is a promising option for cancer treatment, particularly in combination with existing therapies like chemotherapy and immunotherapy. Furthermore, unlike immunotherapy and many targeted therapies, SGLT-2is are cost-effective and have a favorable safety profile, as they are already used in diabetes management without severe side effects. These advantages position SGLT-2is as an ideal candidate for clinical investigation in oncology, especially for patients with comorbidities like diabetes.

SGLT-2is was first developed as an oral hypoglycemic agent; it does not rely on insulin, but possesses a unique mechanism for regulating blood sugar levels [11]. SGLT-2, a member of the sodium symporter family (SSS), is situated within the apical membrane of the S1 segment of the renal proximal tubule [12]. It can mediate the reuptake of most glucose in the glomerular filtrate and reduce plasma glucose levels via an insulin-independent mechanism [13]. Moreover, studies have indicated that SGLT-2is overexpressed in various types of tumor cells and plays a significant role in glucose uptake by tumor cells [14, 15]. SGLT-2is selectively blocks glucose reabsorption in the kidneys, leading to increased urinary glucose elimination (UGE), thereby improving impaired β-cell function and systemic insulin sensitivity [16]. The following SGLT-2is have been developed: dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin. Some studies have shown that SGLT-2is is effective not only for DM, but also shows good therapeutic effects in various diseases, such as hyperuricemia, cardiovascular disease, kidney damage, and chronic kidney disease [17, 18]. In terms of cardioprotection, several previous cardiovascular safety outcome trial (CVOT) studies have demonstrated that the utilization of SGLT-2is decreases hospitalization rates of major cardiovascular events (MACE) in patients with type 2 DM [19, 20]. In terms of benefit to the kidney: two studies had shown that SGLT-2is can reduce the risk of end-stage renal disease and chronic kidney failure [21, 22].

Studies have shown that the risk of cancer is elevated in DM patients. A comprehensive meta-analysis showed that type 2 DM has an increased cancer risk of approximately 10% [23]. The potential underlying mechanisms include genetic factors, obesity, hyperglycemia, and hyperinsulinemia [24]. Furthermore, the relationship between oral antidiabetic medications and cancer remains unclear. Studies have indicated that the traditional antidiabetic drug pioglitazone is associated with a potential increase in the risk of bladder cancer in patients [25]. This has raised concerns regarding the use of SGLT-2is and their potential cancer risk. Glycolysis is the primary means of energy acquisition for tumor cells, driven by the hypoxic microenvironment within tumors and the Warburg effect. In this altered metabolic state, tumor cells preferentially rely on glycolysis for ATP production, even in the presence of oxygen, a phenomenon known as aerobic glycolysis. This metabolic reprogramming supports rapid cell proliferation and survival in the tumor’s hypoxic conditions. Targeting this pathway with SGLT-2 inhibitors may disrupt glucose uptake and metabolism in tumor cells, thereby impairing their energy production. By inhibiting glucose transport, SGLT-2 inhibitors could reduce the availability of glycolytic intermediates, potentially slowing tumor growth and enhancing the efficacy of other therapeutic strategies. High expression of SGLT-2 receptors in various tumor cells, such as colorectal cancer [26], liver cancer [27], and prostate cancer [28], indicates that the SGLT-2 receptor is an important protein in the glycolysis pathway of tumor cells. Therefore, SGLT-2is in cancer treatment has great potential and significance in cancer treatment. Currently, research on SGLT-2is in oncology is intensifying and rapidly advancing, with a focus on evaluating its safety and uncovering its potential anti-tumor effects and mechanisms. Existing research indicates that the use of SGLT-2is does not increase the risk of malignant tumors [29]. However, most available data are derived from preclinical or small-scale clinical studies, and large-scale randomized trials are needed to substantiate their therapeutic role in oncology. Based on existing studies, we analyzed in detail the possible mechanisms underlying the elevated risk of cancer in patients with diabetes and summarized the mechanism of SGLT-2is in the treatment of various types of tumors in recent years. Furthermore, we conducted a comprehensive analysis of the synergistic effects of SGLT-2is in combination with established anti-cancer drugs. Its favorable biosafety profile indicates the significant potential of these agents to emerge as novel therapies for clinical cancer treatment.

Pathophysiological basis: linking diabetes and cancer

SGLT-2is was initially used to manage blood sugar levels in individuals with type 2 DM. Before elaborating the relationship between SGLT-2is and cancer, it is important to mention the intimate association between DM and cancer. From the outset, the DM and SGLT-2is are inherently intertwined. DM is a collection of metabolic disorders characterized by high blood sugar levels and impaired glucose metabolism. Many studies have shown that chronic hyperglycemia can promote tumorigenesis and progression through several mechanisms. First, in the early stages of tumor development, persistent hyperglycemia leads to genetic alterations such as methylation, chromosomal remodeling, and other detrimental changes, resulting in epigenetic modifications that ultimately trigger cancer [30]. Second, hyperglycemia and hyperinsulinemia play crucial roles in cancer proliferation and development, both of which are characteristic features of DM [31]. Thirdly, Adenosine-5’-triphosphate (ATP) and intermediate products generated by glycolysis serve as crucial building blocks for the growth and development of tumor cells [32]. In addition to providing energy and raw materials for tumor cells, high glucose can activate signaling pathways that cause tumor cell proliferation, such as Wnt/β-catenin signaling and epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) signaling [33, 34]. Finally, in advanced stages of tumor development, the promotion of tumor angiogenesis and metastasis is another important mechanism. This involves the activation of the phosphoinositide 3-kinase (PI3K) signaling pathway and protein kinase C-alpha (PKC-α) enzyme, which increases the expression of Akt protein and phospholipase Cγ, and the synthesis of hypoxia-inducible factor-1alpha (HIF-1α) and vascular endothelial growth factor (VEGF) [35–37]. Moreover, high blood glucose levels are associated with resistance to cancer treatment [38]. For instance, elevated glucose levels can reduce the effectiveness of chemotherapeutic drugs like cisplatin and methotrexate by affecting cellular pathways involved in drug uptake and metabolism. [39]. This resistance is partly driven by the activation of signaling pathways like Akt, EGF/EGFR, and PKC-α, which promote tumor cell survival, proliferation, and metastasis. In simpler terms, these pathways help tumor cells adapt to stress, making them less responsive to treatment. Large studies from Japan also show that people with diabetes have a 20% higher risk of developing cancer, supporting the link between diabetes and cancer risk. [40]. The studies have limitations including small sample size, focus on older age groups, and potential influences from unaccounted factors like lifestyle and genetics. These issues suggest the need for further research with larger, diverse populations and longer follow-up to confirm the findings and understand the mechanisms.

Safety considerations: SGLT-2is and cancer risk

Oral antidiabetic medications appear to reduce cancer risk by lowering blood glucose levels. However, during the initial clinical study of dapagliflozin, patients with type 2 DM who used dapagliflozin had an increased incidence of bladder and breast cancers compared with those who did not use dapagliflozin [41]. Therefore, the U.S. Food and Drug Administration (FDA) did not approve it in 2012 [42]. However, animal experiments on dapagliflozin in 2014 disproved previous conclusions, stating that dapagliflozin was not associated with an increased risk of tumors [43]. Subsequently, the FDA approved the use of dapagliflozin [44]. Jonghe et al. investigated the potential carcinogenicity of canagliflozin in a 2-year rat study and observed an increase in pheochromocytomas, renal tubular tumors, and testicular mesenchymal cell tumors [45]. However, they demonstrated that this tumorigenic effect was secondary to carbohydrate malabsorption and not related to canagliflozin exposure for 3 years [46]. It seems that the relationship between SGLT-2is and cancer is not clear, and more time and high-quality research are needed. Since the approval of canagliflozin, the first SGLT-2i, in 2013, SGLT-2is has been clinically tested for several years and many clinical practitioners have explored the relationship between SGLT-2is and cancer. Studies examining the relationship between SGLT-2 inhibitors and cancer risk have produced mixed results. While a meta-analysis of clinical trials (lasting 61 weeks) found no significant increase in overall cancer risk for patients using SGLT-2 inhibitors compared to control groups, there were notable differences between the specific inhibitors [47]. For example, empagliflozin has been linked to a potential increased risk of bladder cancer, while canagliflozin appears to offer protection against gastrointestinal cancers. A meta-analysis by Pelletier et al. (2019) reinforced these findings, highlighting that different SGLT-2 inhibitors may have distinct effects on various cancer types. [48]. Specifically, canagliflozin was associated with a lower risk of gastrointestinal cancer compared to placebo or other treatments, while empagliflozin was linked to a higher incidence of gastrointestinal cancer. These conflicting results suggest that while SGLT-2 inhibitors do not appear to broadly increase cancer risk, their impact may vary depending on the specific drug and cancer type. Further long-term studies are needed to clarify these findings and determine whether certain SGLT-2 inhibitors carry specific cancer risks or protective effects.

In addition, empagliflozin is also associated with an increased risk of bladder cancer. Shi et al. [49] retrieved randomized controlled trials (RCTs) published through August 2020 related to patients with type 2 DM treated with SGLT-2i versus placebo or other glucose-lowering medications. The study suggested that dapagliflozin may increase the overall risk of malignant tumors compared to other oral hypoglycemic agents, whereas empagliflozin may decrease this risk. However, limited by the relatively short follow-up period, information on these factors is incomplete and insufficient to explain the long-term effects of SGLT-2i on malignancy. An inaugural comprehensive study directly compared the effects of SGLT-2i and dipeptidyl peptidase 4 inhibitor (DPP4i) on overall and prespecified cancer risk in a cohort of Asian patients [50]. This study found that SGLT-2i was associated with lower all-cause mortality, cancer-related mortality, and new-onset overall cancer risk than DPP4i was. However, Dicembrini [29] and Spiazzi [51] had different views. Their results showed that SGLT-2is did not affect the incidence of malignancies. Treatment with SGLT-2is did not lead to a notable increase in the occurrence of bladder cancer or any other form of cancer. To elucidate the relationship between SGLT-2is and bladder cancer, Li et al. [52] examined information from the Chang Gung Research Database (CGRD) to determine whether the concurrent use of SGLT-2is and pioglitazone elevated the likelihood of bladder cancer. Their findings indicated that this combination therapy did not correlate with a higher risk of newly detected bladder cancer in individuals with type 2 DM, who had no history or ongoing cases of bladder cancer.

Tumor-specific mechanisms of SGLT-2 inhibitors

From the existing research, most of the studies, including clinical and basic studies, have shown that SGLT-2is can inhibit cancer. For different sites of tumors, SGLT-2is has different anti-tumor mechanisms (Table 1 and Table 2). Moreover, some of these mechanisms are tumor-specific. A summary of these mechanisms will be helpful to researchers. In conclusion, SGLT-2is has promising potential for cancer treatment. We examine the role of SGLT-2is across different tumor types, with a focus on their mechanisms of action and therapeutic potential. SGLT-2 inhibitors have emerged as promising candidates for cancer treatment due to their ability to inhibit glucose uptake in tumor cells, modulate critical signaling pathways, and enhance the efficacy of other therapies. The subsections that follow are organized by tumor site, highlighting the specific effects of SGLT-2 inhibitors in each type of cancer, including lung cancer, hepatocellular carcinoma, breast cancer, and more. Each subsection discusses the unique and shared mechanisms of action of SGLT-2 inhibitors, as well as their potential therapeutic implications for patients with these cancers.

Table 1.

Anticancer mechanisms of SGLT-2is approved for clinical use in different tumors

Tumor type	Cell model	SGLT-2i	Study type	Antitumor mechanisms
Lung cancer	A549 cell (human)	Canagliflozin	In vitro	It can obstruct the mitochondrial respiration and suppress the mTOR-HIF-1α signaling cascade[58]
Hepatocellular carcinoma	HepG2 cell (human)	Canagliflozin	In vitro	It can reduce metastasis, angiogenesis and metabolic reprogramming[63]
Breast cancer	DMBA-induced breast cancer model (rats)	Canagliflozin	In vivo	It can inhibit the mTOR/NLRP3/caspase-1[81]
Pancreatic cancer	Capan-1 and PANC-1 cells (human)/nude mice	Canagliflozin	In vitro/vivo	It can suppress the glycolysis through the PI3K/AKT/mTOR signaling pathway[84]
Gastric cancer	MGC-803 and HGC-27 (human)/nude mice	Canagliflozin	In vitro/vivo	It can inhibit metastasis as a HDAC6 inhibitor[87]
Thyroid cancer	Thyroid cancer cell (human)	Canagliflozin	In vitro	It can reduce the migration and inhibit the formation of colonies[94]
Prostate cancer	Prostate cancer cell (human)	Canagliflozin	In vitro	It can inhibit complex-I supported respiration and cellular proliferation[95]
Renal carcinoma	CaKi-1 cells (human)/nude mice	Dapagliflozin	In vitro/vivo	It can reduce the viability of renal carcinoma cell, regulate the cell cycle and apoptosis[97]
Cervical cancer	HeLa cell and C33A cell (human)/nude mice	Empagliflozin	In vitro/vivo	It can inhibit the migration and induce the apoptosis[99]
Adult T-cell leukemia	MT-1 and MT-2 cell (human)	Luseogliflozin and tofogliflozin	In vitro	It can diminish the absorption of glucose and reduce the levels of ATP and NADPH[101]
Osteosarcoma	Osteosarcoma cell line (human)	Canagliflozin	In vitro	It can inhibit tumor growth and induce immunity by activating the STING/IRF3/IFN-β pathway[102]
Glioblastoma	Glioblastoma cells/mice (human)	Canagliflozin	In vitro/vivo	It can inhibit tumor growth and division by activating AMPK[104]

mTOR mammalian target of rapamycin, HIF-1α hypoxia-inducible factor-1alpha, DMBA 7, 12 di-methyl-benzaanthrathene, NLRP3 nod-like receptor protein 3, PI3K phosphoinositide 3-kinase, HDAC6 histone deacetylase 6, ATP Adenosine-5'-triphosphate, NADPH nicotinamide adenine dinucleotide phosphoric, STING stimulator of interferon genes, IRF3 interferon regulatory factor 3, IFN-β interferon beta, AMPK adenosine monophosphate-activated protein kinase

Table 2.

SGLT-2 inhibitors’ mechanisms in different tumor types

Cancer type	SGLT-2 inhibitor	Mechanisms of action	Key findings
Lung cancer	Canagliflozin	Inhibits glucose uptake, HIF-1α inhibition, EGFR resistance	Decreased tumor volume, improved survival in early-stage lung adenocarcinoma
Hepatocellular carcinoma (HCC)	Canagliflozin	Inhibition of glucose uptake, glycolysis suppression, β-catenin signaling	Reduces tumor metastasis, improves survival, shifts metabolism from glucose to fatty acids
Breast cancer	Dapagliflozin	AMPK/mTOR signaling, apoptosis induction, glutamine metabolism inhibition	Significant reduction in tumor size, synergy with chemotherapy
Pancreatic cancer	Canagliflozin	Suppresses glycolysis, GLUT-1 downregulation, PI3K/AKT/mTOR	Slows tumor growth, increases tumor necrosis
Prostate cancer	Canagliflozin	Mitochondrial complex I inhibition, metabolic reprogramming	Suppresses cancer cell proliferation through mitochondrial dysfunction
Colorectal cancer	Dapagliflozin	Glucose uptake inhibition, synergistic effect with chemotherapy	Improves survival, reduces glucose metabolism in tumors

Lung cancer

Lung cancer is the deadliest cancer in the world [53]. Lung cancers include small cell lung cancer and non-small cell lung cancer (NSCLC). Non-small-cell lung cancers mainly include adenocarcinomas and squamous carcinomas. Scafoglio et al. [15] reported spatiotemporal specificity of glucose uptake in lung adenocarcinoma. SGLT-2 receptor is highly expressed in highly differentiated tumors, whereas glucose transporter 1 (GLUT1) is highly expressed in poorly differentiated tumors. Thus, SGLT-2-mediated glucose transport relies on early stage lung cancer and may play a crucial role in lung cancer progression. In addition, they found that the final tumor volume of treated mice was approximately 47% lower than that of control mice after adjusting for experimental and mouse random effects. They proved that canagliflozin (30 mg/kg/d) for 1 month in cancer-affected mice could reduce the tumor volume in vivo. Thus, SGLT-2is delayed the development and growth of lung adenocarcinoma in a mouse model, suggesting that SGLT-2 inhibition is a potential therapeutic strategy for precancerous and early stage lung adenocarcinoma. However, there are limitations to this study. The observed reduction in tumor size and increased survival in mice might result from decreased blood glucose levels rather than direct inhibition of tumor glucose uptake. More than 60% of non-small cell lung cancers express EGFR [54]. EGFR-tyrosine kinase inhibitor (TKIs) treatment is superior to conventional therapy in EGFR mutation-positive patients [55]. However, the efficacy of these drugs is limited by the development of drug resistance. Li et al. [56] used software to screen for drugs that target EGFR-TKI-resistant tumor cells. They were surprised to find that canagliflozin had anti-tumor effects, promoting apoptosis in a concentration-dependent manner. More importantly, it effectively inhibits the autophosphorylation of EGFR and its downstream pathways in non-small cell lung cancer cells, which is one of the mechanisms by which tumor cells develop resistance to EGFR-TKIs. This study was performed only in cells and further mechanistic and animal studies are required. Lnc AC016727.1/BACH1/HIF-1α signal loop promotes the progression of non-small cell lung cancer (NSCLC) [57]. Biziotis et al. [58] revealed an inhibitory mechanism of canagliflozin. They found that the clinically relevant dose (5–30 μM) of canagliflozin not only inhibits HIF-1ɑ to inhibit the proliferation of NSCLC, but also combines with radiotherapy to achieve better anti-tumor effects. In addition, HDAC2 knockdown improved the antiproliferative ability of canagliflozin in NSCLC cells, and histone deacetylase 2 (HDAC2) is a transcriptional regulator of canagliflozin in the process of anti-tumor proliferation (Fig. 1). Luo et al. [59] conducted a clinical study to evaluate the role of SGLT-2is use and its duration of use on survival in patients with NSCLC. They found that SGLT-2is use was associated with a significantly lower risk of death after adjusting for the covariates. The longer the duration of SGLT-2is use, the lower the risk of death. Moreover, the combined utilization demonstrated a more pronounced association with decreased mortality risk from non-small cell lung cancer, in contrast to the administration of SGLT-2is or metformin.

Fig. 1.

Canagliflozin inhibits the growth of NSCLC through multiple mechanisms. Canagliflozin inhibits complex I and mitochondrial oxidative phosphorylation. (ii) Canagliflozin activates the AMPK/mTOR pathway to inhibit protein synthesis. (iii) Canagliflozin inhibits HDAC2 to reduce HIF-1α levels. (iv) Canagliflozin increased the number of G1 phase cells and inhibited intracellular DNA replication. OxPhos, oxidative phosphorylation; AMPK, adenosine monophosphate-activated protein kinase; mTOR, mammalian target of rapamycin; HDAC2, histone deacetylase 2; HIF-1α, hypoxia-inducible factor-1alpha

In addition to glucose metabolism-related targets, other molecular regulators such as long non-coding RNAs and tumor microenvironment components are also being explored in lung cancer. MALAT1, for instance, has been identified as a key long non-coding RNA that drives lung cancer pathogenesis through modulation of epithelial–mesenchymal transition and immune evasion, and has emerged as a potential therapeutic target [60]. Furthermore, immunotherapeutic innovations such as monoclonal antibodies, viral vaccines, and proteolysis-targeting chimeras (PROTACs) have shown promise in enhancing lung cancer control and may complement metabolic inhibition strategies such as SGLT-2 blockade [61]. Recent studies also highlight the role of molecular targets including osteopontin, EpCAM, estrogen receptor-α, and carbonic anhydrase IX, which can be modulated by nanoparticle-based delivery systems to inhibit lung tumor progression [62]. These findings point to the multifactorial nature of lung cancer pathogenesis and support the rationale for combinatory therapeutic strategies involving SGLT-2 inhibitors.

In conclusion, the above studies have shown that SGLT-2is can inhibit lung cancer at both animal and cellular levels. It inhibits the growth of early stage lung adenocarcinoma by inhibiting the SGLT-2 receptor and the proliferation of NSCLC cells by inhibiting HIF-1α. In addition, it can increase the anti-tumor effect of radiotherapy and attenuate resistance to EGFR-TKIs. A clinical study also demonstrated that the use of SGLT-2is is associated with a reduced risk of death in patients with NSCLC and is more effective in combination with metformin. Overall, it is generally agreed that SGLT-2is has anti-tumor effects in NSCLC.

Hepatocellular carcinoma (HCC)

Primary hepatic malignancies rank sixth in terms of global incidence and are the third most common cause of cancer-related fatalities worldwide [3]. Hepatocellular carcinoma (HCC) has its own characteristics: it is vascularized and has a high recurrence rate. Several studies have elucidated the molecular mechanisms underlying the anticancer effects of canagliflozin in hepatocellular carcinoma (HCC). Kaji et al. [27] demonstrated that canagliflozin inhibits glucose uptake and glycolysis in HCC cells, reducing ATP levels, which are essential for tumor cell growth and proliferation. This inhibition of glucose metabolism triggers a halt in the G2/M phase of the cell cycle and induces apoptosis through caspase-3 activation. Furthermore, canagliflozin reduces tumor load in human HCC xenografts, independently of glycemic status, indicating that its anticancer effects may not rely solely on its glucose-lowering properties. Additionally, canagliflozin affects angiogenesis by decreasing the production of key proangiogenic factors such as IL-8, angiopoietin, and TIMP-1. These changes impair vascular endothelial growth and reduce the proangiogenic activity of HCC cells, which may further suppress tumor progression. Further molecular studies have shown that canagliflozin also inhibits tumor metastasis by altering glycolysis, angiogenesis, and epithelial-to-mesenchymal transition (EMT) pathways, through downregulation of HIF-1α via the AKT/mTOR signaling cascade. Metabolomic analyses also revealed that canagliflozin reprograms metabolic pathways, including oxidative phosphorylation, fatty acid metabolism, and purine/pyrimidine metabolism in HCC cells, enhancing its anti-tumor effects.

Clinically, canagliflozin has shown promising effects in HCC treatment. Luo et al. [63] observed that canagliflozin use was associated with a reduction in HCC metastasis, further supporting its potential as a therapeutic agent in liver cancer. A clinical study by Nakano et al. [64] demonstrated that the use of canagliflozin in HCC patients resulted in improved metabolic reprogramming, suggesting a shift from glucose to alternative energy sources in tumor cells. Furthermore, a clinical trial indicated that canagliflozin significantly reduced mortality risk in patients with advanced HCC by 32%, underscoring its potential as a valuable therapeutic agent in improving patient outcomes. Combined with the studies by Obara [65] and Hung [66], they concluded that alterations in HCC cells were specific to canagliflozin. Hung et al. [66] identified another mechanism of metabolic reprogramming that primarily inhibits cellular glucose utilization in cells. Stimulation of the Wnt/β-catenin signaling pathway enhances aerobic glycolysis in cancer cells [67]. The role of canagliflozin in the inhibition of β-catenin signaling in HCC was demonstrated by Hung MH. Canagliflozin inhibits protein phosphatase 2 A (PP2A)-mediated dephosphorylation of β-catenin to promote β-catenin degradation, and can inhibit glucose uptake by inhibiting glucose inflow in tumor cells, thereby decreasing the upregulation of β-catenin. Therefore, β-catenin signaling has a dual function in inhibiting HCC (Fig. 2). Canagliflozin can also attenuate the maintenance of HCC stem cells and exert anti-tumor effects. Importantly, the ability of canagliflozin to inhibit β-catenin is distinctive among SGLT-2is, and further studies are needed to explain this difference.

Fig. 2.

In HCC, canagliflozin can inhibit tumor growth through dual β-catenin inhibition. Canagliflozin dual β-catenin inhibition. (i) Canagliflozin inhibits GLUT-1, leading to a reduction in glucose influx and subsequent decrease in β-catenin levels. (ii) Canagliflozin inhibits the expression of protein phosphatase 2 A (PP2A), downregulating β-catenin dephosphorylation and reducing β-catenin expression. β-catenin inhibition can decrease CyclinD1 to inhibit tumor growth. GLUT-1, glucose transporter 1; PP2A, protein phosphatase 2A

It has been shown that progressive nonalcoholic steatohepatitis (NASH) increases the risk of HCC [68]. Li et al. observed for the first time that dapagliflozin alleviates lipid accumulation and lipotoxicity by restoring autophagy via the adenosine monophosphate-activated protein kinase (AMPK)–mTOR pathway [69]. SGLT-2is reduce hepatic triglyceride levels by decreasing the insulin-to-glucagon ratio and facilitating the shift from hepatic carbohydrate to fatty acid metabolism [70]. But can SGLT-2is attenuate the progression of NASH to HCC. Yoshioka [71] and Shiba [72]. found that tofogliflozin and canagliflozin protected melanocortin 4 receptor (Mc4r)-mutant mice from liver inflammation and fibrosis, effectively preventing NASH-associated tumors. Additionally, they can inhibit normal hepatocyte senescence. Jojima et al. also found that empagliflozin [73] and canagliflozin [74] improved hepatic steatosis, inflammation, and fibrosis. They also demonstrated that continuous administration of canagliflozin inhibited hepatocarcinogenesis. Observations in the clinical setting were consistent with those of basic research. Kawaguchi et al. [75] observed natural regression of HCC in a patient treated with canagliflozin (100 mg/day) in a clinical setting. They observed the downregulation of angiogenesis-related cytokine expression and hypothesized that this HCC regression might be related to the inhibition of HCC angiogenesis. Hendryx et al. [76] conducted a study using the SEER database to investigate the effect of SGLT-2is on HCC prognosis. It was concluded that the utilization of SGLT-2is was correlated with a substantial 32% decrease in mortality risk in patients with HCC. Stratified analysis by duration of use showed that a longer duration of SGLT-2is use (12 months or longer) was significantly associated with a reduction in mortality compared to no SGLT-2is use.

In conclusion, both basic experiments and clinical data proved that SGLT-2is has anti-tumor effects in HCC. Combined with the characteristics of the liver, the anti-tumor mechanism of SGLT-2is in HCC is also specific. SGLT-2is has a more pronounced effect on angiogenesis in HCC owing to the presence of abundant blood vessels. The liver is a well-known metabolic organ, and metabolic reprogramming is an important mechanism of SGLT-2is in HCC, including glucose, fatty acid, purine, and pyrimidine metabolism. Therefore, SGLT-2is has promising applications in HCC treatment.

Breast cancer

Breast cancer is the leading cause of cancer-related morbidity, disability, and mortality in women, worldwide [77]. Triple-negative breast cancer (TNBC) is one of the most challenging cancers to treat cases. Komatsu et al. [78] found that ipragliflozin (0–50 μM) inhibited breast cancer cell growth. The mechanism behind this is partly that ipragliflozin induces hyperpolarization of the cell membrane, as well as mitochondrial membrane damage. Papadopoli et al. showed that canagliflozin can inhibit the growth of breast cancer cells independently of the SGLT-2 receptor and glucose [79]. However, this mechanism cannot be distinguished from that of mitochondrial disruption or glutamine metabolism. Canagliflozin inhibits mitochondrial respiration in breast cancer cells by inhibiting mitochondrial complex II. In addition, it can decrease the activity of glutamate dehydrogenase by nearly 50%, thereby directly interfering with the glutamine metabolism. In addition, canagliflozin decreased glutamine-mediated anaplerosis by perturbing the citric acid cycle (Fig. 3). Zhou et al. [80] found that SGLT-2is can block the proliferation and growth of human breast cancer cells. The human breast cancer cell line (MCF-7) was inhibited in nude mice fed (100 mg/kg) doses of dapagliflozin, and the size of the tumors was significantly reduced. This is because dapagliflozin inhibits tumor growth by increasing AMPK phosphorylation and decreasing p70S6K phosphorylation in breast cancer, thereby affecting the AMPK/mTOR signaling pathway. SGLT-2is block the G1/G0 phase and induces apoptosis in tumor cells. These findings provide new evidence for the application of SGLT-2is in breast cancer treatment. Sabba et al. [81] also found that mTOR-mediated signaling is involved in the reduction of breast cell tumors by canagliflozin in rats, which supports Zhou’s study [80]. A new mechanism has been proposed by Nalla et al. [82]. Engeletin, an SGLT-2 inhibitor, inactivated specificity protein 1 (Sp1) and pyruvate kinase M2 (PKM2) by enhancing miR-128-3p expression, thereby eliminating breast cancer stemness. Engeletin also promotes CD44⁺/CD24⁺ differentiated cells and reduces tumor cell metastasis. In conclusion, engeletin inhibited tumor growth, proliferation, and metastasis. Nasiri et al. discovered that dapagliflozin slowed tumor growth in a mouse model of obesity-associated triple-negative breast cancer [83]. This is because of its ability to reverse hyperinsulinemia, which leads to decreased glucose uptake and oxidation in tumors. The treatment of triple-negative breast cancer is difficult and lengthy, and SGLT-2is may offer new possibilities.

Fig. 3.

In breast cancer cells, canagliflozin inhibits tumor growth by inhibiting the tricarboxylic acid cycle and glutamine metabolism. Canagliflozin reduced several citric acid cycle intermediates (α-ketoglutarate, succinate, fumarate, malate, and citric acid). It also decreases the activity of glutamate dehydrogenase, thereby inhibiting the conversion of glutamate to α-ketoglutarate. GDH, glutamate dehydrogenase

SGLT-2 in breast cancer involves various SGLT-2is (ipragliflozin, canagliflozin, engeletin, and dapagliflozin). However, but no studies have compared the degree of inhibition in breast cancer. It also involves a variety of anti-tumor mechanisms, the most unique of which is anti-tumor by eliminating the stem cell nature of breast cancer cells, which after all is the way to eliminate tumors at their source. However, more in-depth studies are needed to reveal the anti-tumor mechanisms of SGLT-2is in relation to breast cancer. Overall, the application of SGLT-2is for breast cancer treatment has not yet been established.

Pancreatic cancer

There is an urgent need for new diagnostic and therapeutic tools for pancreatic cancer. Scafoglio et al. [28] found that SGLT-2 receptor is expressed in pancreatic adenocarcinomas. Therefore, an SGLT-specific imaging tool (Me4FDG-PET) can be used to diagnose pancreatic cancer. SGLT-2is is beneficial for the treatment of pancreatic cancer, as it blocks glucose uptake and decreases tumor growth and survival in a pancreatic cancer xenograft model. Xu et al. [84] provided the detailed mechanisms. They found that canagliflozin inhibits pancreatic cancer growth by suppressing glycolysis. This was achieved by downregulating GLUT-1 and lactate dehydrogenase A (LDHA) through the PI3K/AKT/mTOR/HIF-1α signaling pathway at both mRNA and protein levels. Wright [85] used canagliflozin or dapagliflozin at a dose of 30 mg/kg to feed mice to test the effects of SGLT-2is on pancreatic tumor growth and necrosis. They found that both canagliflozin and dapagliflozin increased tumor necrosis by 70%−100%. Surprisingly, they found that canagliflozin significantly reduced tumor growth by 30%, whereas dapagliflozin did not. However, this discrepancy is difficult to explain this discrepancy. A clinical study [86] in Japan showed that SGLT-2is could decrease the risk of pancreatic cancer in patients with T2DM. However, very few patients aged ≥ 65 years were included in the study. Therefore, further studies with larger numbers of participants are highly recommended.

Little research has been conducted on the mechanism of action of SGLT-2is in pancreatic cancer. Xu et al. reported that SGLT-2is only target the SGLT-2 receptor and found that canagliflozin can inhibit glycolysis, thus inhibiting pancreatic cancer growth by inhibiting GLUT-1. However, we have to admit that the use of SGLT-2is in pancreatic cancer treatment seems to have a long way to go, but this study is definitely of great significance.

Gastrointestinal tumors

Jiang et al. found that canagliflozin is a histone deacetylase 6 (HDAC6) inhibitor [87]. Canagliflozin stably binds to HDAC6 and blocks EMT, thereby exerting an inhibitory effect on gastric cancer metastasis in vivo. HDAC6 inhibition can block the proliferation and metastasis of gastric cancer cells [88]. However, the applicability of HDAC6 inhibition to other tumor types remains an area of ongoing research. A study conducted by Kato et al. [89] showed that tofogliflozin significantly inhibited colorectal carcinogenesis in mice with azomethane-induced DM, possibly owing to a reduction in obesity and chronic inflammation. However, tofogliflozin did not affect the proliferation of tumor cells. In contrast, Nasiri et al. [83] concluded in their study of SGLT-2is and obesity-related tumors that dapagliflozin slowed colon cancer tumor growth in an insulin-dependent manner. Furthermore, Chiang et al. [90] demonstrated that SGLT-2is was associated with a higher survival rate in patients with type 2 DM and colorectal cancer. Finally, a study performed by Chan et al. [91] showed that patients taking SGLT-2i had a lower risk of colorectal cancer than those taking DPP4i.

In exploring the relationship between SGLT-2is and gastrointestinal tumors, Jiang et al. revealed a new anti-tumor mechanism. They found that SGLT-2is, which is also an HDAC6 inhibitor, could inhibit gastric cancer metastasis. Whether this mechanism can be generalized for the treatment of other tumors requires further research. Similarly, HDAC2 knockdown improved the antiproliferative ability of canagliflozin in NSCLC cells [58]. In conclusion, the current study shows that SGLT-2is can improve the survival rate of patients with colorectal cancer and DM.

Thyroid cancer

Wang et al. [68] showed that SGLT-2is attenuated thyroid cancer cell growth in vitro and in vivo. Canagliflozin inhibited glucose uptake, glycolysis, and AKT/mTOR signaling activation, and increased AMPK activation in thyroid cancer cells. Furthermore, canagliflozin not only blocked the G1/S phase transition, but also reduced the expression of multiple cyclin proteins in thyroid cancer cells, while concurrently promoting apoptosis. Elevated levels of cyclin D1 [92] and cyclin D3 [93] can promote the development and progression. Coperchini et al. [94] found that canagliflozin could inhibit the formation of colonies by thyroid cancer cells while simultaneously inhibiting the secretion of pro-tumor chemokines, including C-X-C motif ligand 8 (CXCL8) and C–C motif chemokine ligand 2 (CCL2), to inhibit the metastasis of thyroid cancer cells.

In conclusion, SGLT-2 inhibition may limit glucose uptake, leading to oxidative stress-mediated DNA damage and energetic crisis following cell cycle arrest, resulting in increased apoptosis and decreased proliferation of thyroid cancer cells. It can also inhibit tumor cell colony formation and metastasis. However, there is a lack of validation in clinical studies.

Prostate cancer

Prostate cancer is the leading form of cancer affecting the male reproductive and urinary systems. Research conducted by Villani et al. [95] demonstrated that therapeutic levels of canagliflozin, but not dapagliflozin, suppressed the proliferation of prostate cancer cells. Canagliflozin inhibits mitochondrial complex I, which disrupts the electron transport chain and decreases oxygen intake in cancer cells. This inhibition of mitochondrial function contributes to reduced glucose metabolism and limits cancer cell proliferation [96]. Interestingly, dapagliflozin does not appear to inhibit mitochondrial complex I in the same way. One possible reason for this difference could be variations in their molecular structures or binding affinities for the complex I protein. Canagliflozin’s ability to inhibit both complex I and mitochondrial glutamate dehydrogenase suggests a broader impact on mitochondrial metabolism, whereas dapagliflozin may act through different metabolic pathways, potentially targeting glucose uptake more directly without affecting mitochondrial function. Further studies are needed to explore the underlying mechanisms that differentiate the effects of these two SGLT-2 inhibitors on mitochondrial metabolism.

However, animal models, while informative, have limitations in translating findings to human clinical settings due to differences in tumor biology, immune responses, and pharmacokinetics. For clinical validation, the next steps would include conducting phase I trials to assess the safety, tolerability, and optimal dosing of canagliflozin in human cancer patients. Following this, phase II trials would evaluate its efficacy in combination with existing cancer therapies, focusing on endpoints such as progression-free survival and overall survival. Phase III trials in larger, more diverse patient populations will be necessary to confirm these results and establish clinical guidelines for canagliflozin use in cancer treatment. Additionally, identifying biomarkers to monitor patient response and optimize treatment regimens will be essential for clinical success.

Previous studies have suggested that energy plays a pivotal role in the relationship between SGLT-2is and prostate cancer. However, it is worth investigating why canagliflozin inhibits prostate cancer by inhibiting mitochondrial complex I, whereas dapagliflozin does not. It is certain that inhibition of glycolysis is not always the mechanism by which SGLT-2is inhibit prostate cancer growth.

Renal cancer

A study conducted by Kuang et al. [97] showed that dapagliflozin (2 μM) reduced the viability of renal cancer cells because it causes apoptosis and reducing glucose uptake by tumor cells. In addition, they demonstrated that dapagliflozin can shrink tumors, which brings new possibilities for the treatment of renal cancer. However, this needs to be verified clinically. However, compared with other types of tumors, the mechanism of renal cancer inhibition is relatively single. However, the mechanisms underlying inhibition of kidney cancer remain unclear.

Cervical cancer

As the fourth most common cancer in terms of incidence and mortality among women worldwide, cervical cancer poses a significant public health challenge [98]. Xie et al. [99] found that empagliflozin inhibited migration and induced apoptosis of HeLa cells by activating the AMPK/FOXA1 (forkhead box A1) pathway and inhibiting the expression of Sonic Hedgehog (SHH) signaling molecules. They also discovered that engeletin inhibited tumorigenicity, suppressed tumor tissue proliferation, and promoted apoptosis in nude mice. However, this approach has been limited to animal studies. Therefore, clinical studies demonstrating that empagliflozin inhibits cervical cancer in humans are lacking.

Adult T-cell leukemia

Adult T-cell leukemia (ATL) is one of the most refractory blood cancers in humans [100]. The prognosis for patients with ATL remains poor. MT-1 and MT-2 are two ATL cell lines. Nakachi et al. [101] found that two SGLT-2is, luseogliflozin and tofogliflozin, significantly inhibited MT-1 and MT-2 cell proliferation. This may be related to the fact that SGLT-2is significantly reduced the absorption of glucose, as well as the levels of ATP and nicotinamide adenine dinucleotide phosphate (NADPH) in MT-2 cells. In clinical trials, luseogliflozin significantly inhibited the proliferation of ATL cells in acute-type patients at a concentration of 100 μM compared with chronic-type patients. The SGLT-2is may serve as an adjuvant therapy for patients with elevated ALT levels.

Osteosarcoma

Osteosarcoma is a malignant bone tumor that occurs in adolescents. In Wu’s study [102], the SGLT-2 receptor was found to be overexpressed at the protein level in osteosarcoma. They demonstrated that SGLT-2is markedly suppressed the expansion of osteosarcoma tumors and provoked the infiltration of immune cells in living organisms by increasing the activity of the stimulator of interferon genes (STING) pathway. Moreover, Wu et al. discovered that therapy with SGLT-2is could elevate STING expression by suppressing the AKT signaling cascade, thereby triggering the STING/IRF3 (interferon regulatory factor 3)/IFN-β (interferon beta) pathway to produce anti-cancer effects (Fig. 4). Therefore, SGLT-2is is a potential novel therapeutic agent for osteosarcoma treatment.

Fig. 4.

SGLT-2is activate the STING/IRF3/IFN-β pathway, thereby inhibiting the growth of osteosarcoma tumor cells. SGLT-2is inhibit AKT phosphorylation to promote STING upregulation. SGLT-2is also directly promotes STING upregulation to activate the STING/IRF3/IFN-β pathway, which inhibits tumor cell growth and induces immune infiltration. SGLT-2i, sodium-glucose cotransporter-2 inhibitor; STING, stimulator of interferon genes; IRF3, interferon regulatory factor 3; IFN-β: interferon beta

Glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor of the central nervous system with a poor prognosis [103]. Shoda et al. [104] showed that SGLT-2 receptor is expressed in GBM cell lines and GBM specimens. They showed that canagliflozin treatment suppresses the proliferation and expansion of GBM cell lines and mice by enhancing AMPK phosphorylation. Chinyama et al. [105] used molecular docking analysis to confirm that dapagliflozin is a potential therapeutic agent targeting CDK1 (Cyclin-dependent kinases 1)/PDZ binding kinase)/CHEK1 (Checkpoint Kinase 1) in GBM. Overexpression of CDK1/PBK/CHEK1 is associated with advanced GBM and low survival, which can facilitate immune system avoidance and increase the risk of GBM malignancy. Therefore, SGLT-2is may serve as a promising therapeutic agent for GBM.

Human hepatoblastoma

Hepatoblastoma is the most prevalent form of liver cancer in pediatric patients [106]. Wang et al. [107] reported that human hepatoblastomas are interesting. Their study showed that trilobatin, a novel SGLT-1/2 inhibitor, attenuates glucose uptake but also specifically triggers cell multiplication in human hepatoblastoma cells. This suggests that not all SGLT inhibitors inhibit the proliferation of tumor cells or that SGLT-2is does not rely solely on lowering blood glucose to suppress tumors. Further studies are required to evaluate the anticancer mechanisms and the potential of these compounds.

Combination strategies and therapeutic synergies

SGLT-2i can not only be anti-tumor by itself, but can also be combined with other therapeutic means to combat tumor. It has the following functions: 1) direct synergization with other therapeutic agents to inhibit tumor growth. 2) Attenuation of chemotherapy resistance in tumors. 3) Reduce the side effects of other medicines, including those affecting the heart and kidneys.

Synergistic inhibition of tumor growth

SGLT-2is can work synergistically with chemotherapeutic agents to treat tumors (Table 3). Scafoglio et al. [28] conducted a compelling study wherein gemcitabine and canagliflozin were administered to a murine model of pancreatic cancer. Both drugs were found to slow tumor growth; however, canagliflozin increased necrosis in the center of the tumor, whereas gemcitabine did not. This is because gemcitabine exerts anti-tumor effects by inhibiting DNA synthesis and ribonucleotide reductase, leading to the depletion of deoxyribonucleotides in cells and cell cycle arrest [108]. Canagliflozin enhances gemcitabine's anticancer effects by engaging complementary mechanisms. Akingbesote et al. [109] demonstrated that both paclitaxel and dapagliflozin reduce glucose uptake in tumors and improve survival. Dapagliflozin and paclitaxel showed cumulative effects of reducing tumor glucose uptake and improving survival in two breast cancer mouse models. Longaray et al. [110] suggested that the combination of dapagliflozin with paclitaxel and purinergic inhibitors may be an effective and intermittent therapeutic strategy for triple-negative and estrogen receptor-positive breast cancers. SGLT-2is can exert synergistic anti-tumor effects with targeted agents. Okada et al. [26] discovered that the combination of dapagliflozin (5 mg/day) and cetuximab reduced the dimensions of metastases and the concentrations of carcinoembryonic antigens in a patient with colon cancer that had spread to the liver.

Table 3.

Antitumor effects of different SGLT-2is in synergy with other anti-tumor approaches in different tumors

SGLT-2i	Collaborator	Type of collaborator	Tumor type	Synergistic anti-tumor mechanisms
Canagliflozin	Gemcitabine	Chemotherapeutic agent	Pancreatic cancer	They can slow tumor growth by increasing necrosis and promote cell cycle arrest[28]
Dapagliflozin	Paclitaxel	Chemotherapeutic agent	Breast cancer	They can reduce tumor glucose uptake and improve survival[109]
Dapagliflozin	Paclitaxel	Chemotherapeutic agent	Triple-negative breast cancer	They can cause cell cycle arrest and apoptosis/necrosis[110]
Dapagliflozin	Cetuximab	Targeted drug	Colon cancer with liver metastasis	They can significantly reduce metastasis size and carcinoembryonic antigen levels[26]
Canagliflozin	Sorafenib	Targeted drug	Hepatocellular carcinoma	They can effectively inhibit tumor growth[111]
Empagliflozin	Ipilimumab	Immune checkpoint inhibitor	Breast cancer	It can reduce drug cytotoxicity and combat tumor[112]
Canagliflozin	Radiotherapy	Radiotherapy	Prostate cancer	It can block mitochondrial respiration, inhibit the mTORC1-HIF-1α pathway and promote sensitivity to radiotherapy[113]

mTORC1 Mechanistic target of rapamycin complex 1, HIF-1α hypoxia-inducible factor-1alpha

Therefore, SGLT-2is could serve as a potential adjuvant drug for the treatment of advanced colon cancer. Zhou et al. [111] found that the combination of canagliflozin (20 μM) and sorafenib effectively inhibited tumor growth in HCC xenografted nude mice. SGLT-2is can synergistically exert anti-tumor effects, together with immune checkpoint inhibitors. Empagliflozin, under conditions of high blood sugar, enhances anti-tumor effectiveness and reduces the toxic impact of ipilimumab, an inhibitor of cytotoxic T lymphocyte-associated protein 4 (CTLA-4), on breast cancer cells [112]. Finally, SGLT-2is can synergize with radiotherapy to treat tumors. Ali et al. [113] showed that the antidiabetic drug canagliflozin promotes sensitivity to radiotherapy in prostate cancer by blocking mitochondrial respiration and inhibiting the mTORC1 (Mechanistic target of rapamycin complex 1)-HIF-1α pathway. In conclusion, SGLT-2is can play an important role in tumor inhibition using chemotherapeutic agents, targeted agents, immune checkpoint inhibitors, and radiotherapy.

While all three inhibitors, canagliflozin, dapagliflozin, and engeletin, demonstrate anti-tumor potential, their mechanisms and efficacy vary. Canagliflozin excels in reducing glucose uptake and inducing necrosis, particularly in pancreatic and gastrointestinal cancers. Dapagliflozin, on the other hand, has shown enhanced efficacy when combined with conventional chemotherapeutic agents like paclitaxel, particularly in breast cancer. Engeletin stands out for its ability to target cancer stem cells and reduce metastasis in breast cancer, highlighting its distinct mechanism compared to the other inhibitors. These differences suggest that a more tailored approach, considering the specific inhibitor’s strengths, may enhance treatment strategies depending on the cancer type.

Attenuating chemotherapy resistance in tumors

In addition to the direct inhibition of tumor growth, SGLT-2is can also attenuate tumor resistance to chemotherapeutic agents and play an indirect anti-tumor role. Zeng et al. [114] found that canagliflozin inhibits the malignant behavior of HCC and attenuates its resistance to chemotherapeutic agents. Mechanistically, PKM2 can combine c-Myc to reduce the phosphorylation of c-Myc Thr58. The phosphorylation of c-Myc Thr58 can promote its degradation through ubiquitination. Canagliflozin inhibited intracellular aerobic glycolysis in HCC cells by downregulating PKM2, leading to a decrease in c-Myc. This process consequently diminishes the expression of glutaminase 1 (GLS1), an essential enzyme involved in glutamine metabolism, resulting in disruption of glutamine utilization. Both inhibition of glycolysis and lack of intracellular glutamine induced iron death in HCC cells, re-sensitizing HCC cells to cisplatin (Fig. 5). Zhong et al. [115] discovered that canagliflozin could suppress the development of resistance to doxorubicin (Dox) by impeding the activity of P-glycoprotein (P-gp) and autophagy in HepG2 cells. P-gp actively expels chemotherapeutic agents from within the cell, diminishing the concentration of the drug inside, which enables tumor cells to avoid damage, and may even lead to the development of chemoresistance. Autophagic processes safeguard tumor cells from the lethal effects of chemotherapy; therefore, the regulation of autophagy is an important strategy to prevent tumor growth. These findings suggest that canagliflozin may serve as a promising agent to ameliorate Dox chemoresistance in tumor treatment. In addition, dapagliflozin reduces cisplatin resistance in hepatoblastoma [116].

Fig. 5.

Synergistic anti-tumor mechanism of canagliflozin and cisplatin. PKM2 can combine c-Myc to reduce the phosphorylation of c-Myc Thr58. The phosphorylation of c-Myc Thr58 can promote its degradation through ubiquitination. The combined action of canagliflozin and cisplatin leads to a decrease in PKM2, which increases the degradation of c-Myc, leading to a decreased transcription of glutaminase1 (GLS1). The decrease in GLS1 inhibits the conversion of glutamine to glutamate, leading to a decrease in GSH, which induces ferroptosis. Canagliflozin reduces the chemoresistance of HCC to cisplatin and acts as an anti-tumor agent. PKM2, pyruvate kinase M2; GLS1, glutaminase 1; GSH, glutathione

Emerging evidence also points to the role of histone deacetylase (HDAC) inhibition as a strategy to overcome chemoresistance. For instance, rhamnetin, a flavonoid nutraceutical compound, has been shown to arrest the cell cycle of ovarian cancer cells via inhibition of HDAC2, a protein associated with drug resistance and tumor proliferation [117]. This supports the notion that HDAC2 could be a shared target in SGLT-2i-enhanced anti-tumor strategies, as previous studies have demonstrated HDAC2 involvement in modulating canagliflozin’s efficacy. Furthermore, the development of polyphenol-loaded nanocarriers offers another potential avenue to enhance drug delivery and sensitize resistant tumors. These delivery platforms have been shown to improve the bioavailability and cellular uptake of natural compounds with anti-cancer potential, such as polyphenols, and may be combined with metabolic agents like SGLT-2is for synergistic effects [118]. These concepts warrant further exploration in the context of combination regimens for drug-resistant tumors.

Attenuate the cardiac and renal side effects of other drugs against tumors

Reduce the cardiac side effects of anti-tumor drugs

Gongora et al. [119] first investigated the possible cardioprotective effects of SGLT-2is in patients with cancer patients undergoing anthracycline-based chemotherapy. They found that use of SGLT-2is correlated with a lower frequency of heart-related complications. Cardiac events included incidence of heart failure, hospital admission for heart failure, development of cardiomyopathy, and clinically significant arrhythmias. This finding was confirmed by Abdel-Qadir's study [120]. According to Avula's findings [121], compared to those undergoing standard guideline-directed medical treatment (GDMT) without SGLT-2is, patients with cancer therapy-related cardiac dysfunction and heart failure(HF) who received SGLT-2is have a decreased likelihood of acute worsening of HF, overall mortality, hospital admissions or emergency department visits, episodes of atrial fibrillation, or atrial flutter. Many researchers have explored why SGLT-2is is beneficial in terms of cardiac side effects of chemotherapeutic agents. Most of these studies focused on DOX-induced cardiotoxicity. Belen et al. [122] discovered that dapagliflozin administration mitigated cardiac failure and pathological alterations induced by Dox in non-diabetic rodents. This finding indicated that dapagliflozin has potential as a preventive measure against heart damage that can arise from cancer therapy. Bora et al. [123] found that dapagliflozin and empagliflozin could preserve hypertrophic parameters and attenuate cardiac atrophy-induced gene expression, thereby improving serum biochemical markers and hemodynamic parameters. Chang et al. [124] also found in a rat cardiotoxicity model that dapagliflozin (10 mg/kg/d) enhanced heart function impaired by Dox and reduced the fibrosis and cell death in the heart. Mechanistically, this may be related to the fact that dapagliflozin reduces the production of reactive oxygen species (ROS) and cell death triggered by Dox through the intervention of STAT3 (the signal transducer and activator of transcription 3) in heart muscle cells. Hsieh et al. [125] observed that dapagliflozin (20 μM) following Dox exposure stimulates the PI3K/AKT pathway in H9c2 cardiomyocytes. This activation subsequently promotes an increase in the expression of antioxidant proteins along with the improvement of mitochondrial function through the activation of Nrf2. Furthermore, the reduction in oxidative stress led to downregulation of hypertrophy markers (ANP and BNP) and fibrosis. Additionally, the levels of the pro-inflammatory cytokine IL-8 decreased following dapagliflozin treatment, which may have been facilitated through the PI3K/AKT/Nrf2/p38/NF-κB signaling pathways. Kim et al. [126] also found that low-dose angiotensin receptor-neprilysin inhibitor (ARNI, 34 mg/kg/day) combined with SGLT-2i (1 mg/kg/day) delayed survival in mice. Cardiac insufficiency can be restored by improving cardiac systolic function and left ventricular structural remodeling in Dox-injected mice. Dox is cardiotoxic, causing thinning of myofibrils and cytoplasmic vacuolization in the heart as well as reduced expression of cardiac structural proteins and myosin-binding proteins, leading to cardiac atrophy. Low-dose ARNI combined with SGLT-2i reversed these changes. In this preclinical model, low-dose ARNI in combination with SGLT-2i had a significant therapeutic effect on the cardiotoxicity caused by Dox. However, whether this combination affects the efficacy of Dox chemotherapy is also an important question. Avagimyan et al. [127] found that dapagliflozin (0.9 mg/kg/d) in Dox + cyclophosphamide (AC) mode protected the heart from chemotherapy-induced cardiomyopathy in a rat model. The molecular mechanism of myocardial protection involves normalization of the redox system, cholesterol metabolism, and stabilization of endothelial function. Min et al. [128] showed that empagliflozin (1μM) could treat trastuzumab (TZM)-induced cardiotoxicity (including cardiac remodeling and systolic dysfunction) in a mouse model by suppressing DNA damage and ferroptosis. Dabour et al. [129] found that canagliflozin attenuates the apoptotic effects of carfilzomib in cardiovascular endothelial cells via AMPK-dependent pathways, thereby mitigating cardiovascular toxicity. Importantly, carfilzomib did not diminish the cytotoxic effects of carfilzomib on cancer cells.

Reduce the renal side effects of anti-tumor drugs

Many anti-tumor drugs also exhibit nephrotoxicity, which leads to renal dysfunction. It has been shown that SGLT-2is are also nephroprotective during anti-tumor processes. Fages et al. [130] reported an interesting case of reduced urine protein with dapagliflozin in a patient with thyroid cancer who received the tyrosine kinase inhibitor, lenvatinib. Chang et al. [131] found that in a cellular model of doxorubicin-induced nephrotoxicity, dapagliflozin (10 mg/kg/d) significantly reduced Dox-triggered renal apoptosis and ROS, attenuating Dox-induced inhibition of PI3K/AKT/eNOS (endothelial nitric oxide synthase (eNOS) expression. Song et al. [132] demonstrated that canagliflozin significantly attenuates cisplatin-induced nephropathy and inhibits apoptosis of renal proximal tubular cells in C57BL/6 mice in vitro. The protective effect of canagliflozin was associated with inhibition of p53, p38, and JNK activation. Mechanistically, canagliflozin partially reduced cisplatin uptake by renal tubular cells in the mouse kidney tissues. Moreover, canagliflozin promotes Akt activation and blocks the mitochondrial apoptotic pathway during cisplatin treatment. Importantly, canagliflozin did not interfere with the therapeutic effectiveness of cisplatin in lung and colon cancer cells. Therefore, the therapeutic role of SGLT-2is in the nephrotoxicity of anti-tumor drugs shows great promise in anti-tumor applications. However, the underlying mechanism requires further investigation.

Overall, SGLT-2is, mostly canagliflozin, has anti-tumor effects on tumors at various sites. A review of the anti-tumor mechanisms of SGLT-2is reveals a number of common mechanisms, as well as a few unique mechanisms for specific tumors. This may not only provide a new approach to anti-tumor therapy, but also inspire the exploration of new anti-tumor approaches. In addition to working alone, SGLT-2is can also work with other anti-tumor methods. They improve the anti-tumor efficacy and the prognosis for tumor patients. More importantly, SGLT-2is can alleviate the cardiac and renal side effects of treatment in patients with cancer, adding another scenario for its use in cancer applications.

Study limitations and future research directions

Although this narrative review integrates current findings on SGLT-2 inhibitors in oncology, several limitations remain. First, most available data are derived from preclinical or small-scale clinical studies, limiting the generalizability of conclusions. Second, the absence of standardized study protocols and varying experimental conditions across studies hinders direct comparisons. Third, publication bias may overrepresent positive findings. Future research should focus on multi-center randomized trials, tumor-type specific mechanisms, and pharmacodynamic modeling to optimize clinical integration of SGLT-2is in oncology.

Conclusion

Cancer is one of the most challenging and difficult-to-treat conditions in clinical medicine worldwide. Therefore, it is essential to explore new anti-cancer treatment strategies, such as the anti-tumor mechanisms of SGLT-2is. We comprehensively summarized the inhibitory effects of SGLT-2is on various tumors and described its benefits in cancer patients when used as an adjuvant therapy in combination with other anti-tumor therapies. Additionally, the long-term safety profile of SGLT-2is in oncology remains poorly defined, particularly regarding their use in patients undergoing concurrent chemotherapy, radiotherapy, or immunotherapy. Most available safety data are derived from diabetic populations without malignancies, which may not be directly translatable to cancer patients. Furthermore, the optimal route and timing of administration—whether continuous or intermittent, oral or intravenous—have not been systematically evaluated in cancer-specific settings. These uncertainties complicate the integration of SGLT-2is into existing oncology treatment protocols, where drug–drug interactions and organ function limitations must be carefully considered.

However, the optimal dosages of SGLT-2is for suppressing tumors and controlling blood glucose remain unestablished. Notably, there is a lack of specific dosage guidelines for using SGLT-2is in cancer patients without diabetes. Given that most existing pharmacokinetic and pharmacodynamic data were derived from diabetic populations, the applicability of these dosages to non-diabetic oncology settings is uncertain. Furthermore, cancer patients often experience altered metabolism, malnutrition, and organ dysfunction due to disease progression or chemotherapy, which could significantly influence drug absorption, distribution, and clearance. Thus, future studies should focus on stratified dose–response evaluations in both diabetic and non-diabetic cancer cohorts to guide safe and effective clinical implementation. More research is needed on the mode of administration, safety, and clinical feasibility of using SGLT-2is. We expect that SGLT-2is will bring new hope to patients with cancer in clinical practice. However, despite encouraging findings from preclinical and small-scale clinical studies, large-scale randomized controlled trials are urgently needed to validate the efficacy and safety of SGLT-2is in diverse cancer populations.

Abbreviations

SGLT-2is

Sodium-glucose cotransporter-2 inhibitors

DM

Diabetes mellitus

UGE

Urinary glucose elimination

CVOT

Cardiovascular safety outcome trial

MACE

Major cardiovascular events

ATP

Adenosine-5'-triphosphate

EGF/EGFR

Epidermal growth factor/epidermal growth factor receptor

PI3K

Phosphoinositide 3-kinase

PKC-α

Protein kinase C-alpha

HIF-1α

Hypoxia-inducible factor-1alpha

VEGF

Vascular endothelial growth factor

FDA

Food and drug administration

RCTs

Randomized controlled trials

DPP4i

Dipeptidyl peptidase 4 inhibitor

CGRD

Chang gung research database

NSCLC

Non-small cell lung cancer

GLUT1

Glucose transporter 1

TKIs

Tyrosine kinase inhibitor

HCC

Hepatocellular carcinoma

IL-8

Interleukin-8

EMT

Epithelial-to-mesenchymal transition

mTOR

Mammalian target of rapamycin

iMPAQT

Metabolomics and absolute quantitative proteomics

PP2A

Protein phosphatase 2A

NASH

Nonalcoholic steatohepatitis

AMPK

Adenosine monophosphate-activated protein kinase

Mc4r

Melanocortin 4 receptor

Sp1

Specificity protein 1

PKM2

Pyruvate kinase M2

HDAC6

Histone deacetylase 6

CXCL8

C-X-C motif ligand 8

CCL2

C–C motif chemokine ligand 2

FOXA1

Forkhead box A1

ATL

Adult T-cell leukemia

STING

Stimulator of interferon genes

IRF3

Interferon regulatory factor 3

IFN-β

Interferon beta

GBM

Glioblastoma multiforme

CDK1

Cyclin-dependent kinases 1

CHEK1

Checkpoint kinase 1

CTLA-4

Cytotoxic T lymphocyte-associated protein 4

mTORC1

Mechanistic target of rapamycin complex 1

GLS1

Glutaminase 1

Dox

Doxorubicin

P-gp

P-glycoprotein

GDMT

Guideline-directed medical treatment

HF

Heart failure

eNOS

Endothelial nitric oxide synthase

Author contributions

JXL and JQ drafted the manuscript. STZ, JHZ, and CYK collected related references and illustrated the figures. YQL, YTL, and YJ collected related references and illustrated the tables. CLB and AXZ conceived of the study and edited the manuscript. All the authors have read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No.82172215, 82072267 and 82272271), GuangDong Basic and Applied Basic Research Foundation (No.2023A1515220073 and 2023A1515220069), Shenzhen Science and Technology Innovation Program (No.JCYJ20230807111302006 and JCYJ20240813150644056), Futian Healthcare Research Project (No.FTWS2023008, FTWS2023056 and FTWS013), Sun Yat-Sen Eighth Affiliated Hospital Clinical Research Program (No.ZDBY-IIT-202304–055).

Availability of data and materials

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.