Sodium-Glucose Cotransporter 2 Inhibitors as Emerging Anticancer Agents

Functional expression of SGLT2 in cancer and its role in tumor glucose uptake

Aberrant glucose metabolism is a hallmark of cancer, with tumor cells relying on glycolysis even under aerobic conditions (Warburg effect) [18]. Although glucose transporter (GLUT) family members, especially GLUT1, are traditionally recognized as the principal GLUTs in tumors [19], increasing evidence shows that SGLTs also contribute to malignant glucose uptake.

A landmark study demonstrated functional expression of SGLT1 and SGLT2 in human pancreatic and prostate cancers [8], confirmed by immunohistochemistry (IHC). Crucially, active SGLT-mediated glucose uptake was confirmed ex vivo in fresh human tumor slices, while SGLT-dependent uptake of α-methyl-4-deoxy-4-[18F]fluoro-D-glucopyranoside (Me4FDG)—a positron emission tomography (PET) tracer specific for SGLT activity—was validated in pancreatic ductal adenocarcinoma (PDAC) and prostate cancer mouse xenograft models [8]. More recently, immunohistochemical analysis of human hepatocellular carcinoma (HCC) tissues revealed that SGLT2 protein levels are significantly upregulated compared to adjacent non-cancerous tissues [20], establishing a clinical basis for targeting this transporter in liver cancer.

In breast cancer, SGLT2 expression has been confirmed at the mRNA and protein levels in cell lines, and pharmacologic inhibition with ipragliflozin suppressed Michigan Cancer Foundation-7 (MCF-7) cell (human breast cancer cell line) proliferation in a dose-dependent manner [21]. This effect was abolished by SGLT2 knockdown, directly linking SGLT2 to tumor glucose transport [21]. Similarly, human colorectal cancer (CRC) cell lines (HCT116, HT-29) express SGLT2, and inhibition with canagliflozin impaired glucose metabolism and reduced survival [10]. In osteosarcoma, SGLT2 was found to be overexpressed at the protein level in human tumor tissues, though not at the mRNA level, suggesting post-transcriptional regulation, and inhibition reduced tumor progression in a syngeneic mouse model [15].

Collectively, these findings demonstrate that SGLT2 is functionally expressed in several solid tumors and represents a potential therapeutic target. Contextualizing the role of SGLT2 relative to the GLUT family is important. Although GLUT1 remains the predominant mediator of bulk glucose uptake in most glycolytic tumors, SGLT2 likely serves a specialized, auxiliary role. Unlike facilitative GLUT transporters which require a concentration gradient, SGLT2 actively transports glucose against a gradient using the sodium motive force. Thus, although SGLT2 may be a minor contributor to total glucose flux in high-glucose environments, it could provide a critical survival advantage in nutrient-deprived tumor microenvironments. Therefore, inhibiting SGLT2 does not merely reduce total calorie intake but specifically disrupts this active transport mechanism, potentially triggering unique metabolic stress signals not achieved by GLUT inhibition alone. Furthermore, Me4FDG-PET imaging may aid in patient stratification for clinical trials, identifying those most likely to benefit from SGLT2-targeted therapy.

Mitochondrial complex I inhibition by SGLT2 inhibitors and downstream AMPK activation

Beyond glucose transport, SGLT2 inhibitors exert direct metabolic effects on mitochondria. Canagliflozin has been shown to inhibit mitochondrial complex I-supported respiration, lowering adenosine triphosphate (ATP) levels and increasing the adenosine monophosphate/ATP ratio [22,23]. This energetic stress activates AMPK, a central regulator that suppresses anabolic processes and promotes catabolic pathways [22].

AMPK activation inhibits downstream oncogenic signals, including the mechanistic target of rapamycin complex 1 (mTORC1) pathway, lipid and protein synthesis, and cell-cycle progression. In human prostate cancer PC3 cells and xenografts, canagliflozin induced AMPK phosphorylation, reduced mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) activity, and enhanced apoptotic signaling [13]. In pancreatic cancer cell lines and xenografts, SGLT2 inhibition has been shown to downregulate GLUT1 and lactate dehydrogenase A (LDHA) via suppression of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway, thereby suppressing glycolysis [24]. In human CRC cell lines, canagliflozin triggered mitochondrial dysfunction and endoplasmic reticulum (ER) stress-associated autophagy, effects linked to sirtuin 3 (SIRT3) upregulation [10].

Importantly, recent findings indicate that the mechanism of mTOR inhibition may vary between drugs. While canagliflozin acts primarily through mitochondrial stress in cell models, Rao et al. [20] demonstrated that empagliflozin directly binds to mTOR, inhibiting its phosphorylation and downstream signaling in BRL and HepG2 cell lines and c-Myc-driven HCC mouse models. However, it must be noted that while these signaling modulations are robust in preclinical settings, direct evidence of SGLT2i-mediated AMPK activation or mTOR inhibition in human tumor biopsies is currently lacking.

A critical challenge in translating these findings is the pharmacokinetic profile. While mitochondrial complex I inhibition in vitro typically requires 10 to 100 μM, the peak plasma concentrations (Cmax) achieved with standard therapeutic doses in humans vary significantly among SGLT2 inhibitors. For example, canagliflozin reaches a Cmax of approximately 10 μM, whereas dapagliflozin and empagliflozin reach only sub-micromolar ranges 0.3 to 0.6 μM [23]. Thus, direct mitochondrial inhibition may represent an off-target effect that is not achievable systemically. However, two possibilities exist for clinical relevance. First, because SGLT2 is functionally overexpressed in specific tumors (e.g., pancreatic and prostate adenocarcinomas) [8], continuous active transport could theoretically lead to intracellular drug accumulation significantly exceeding plasma levels. Second, the indirect systemic pathway is perhaps more pharmacologically plausible at current doses used. By lowering systemic glucose and insulin levels, SGLT2 inhibitors may counteract the mitogenic effects of hyperinsulinemia—a known driver of PI3K/AKT/mTOR signaling in breast and colon cancers—without requiring supra-pharmacological concentrations within the tumor itself [25,26]. Thus, although direct cytotoxicity is possible via local accumulation, the systemic metabolic modulation remains the most robust mechanism at approved doses.

Enhancement of antitumor immune responses by SGLT2 inhibition

SGLT2 inhibitors influence tumor immune evasion, particularly through regulation of PD-L1 stability. A recent study showed that SGLT2 colocalizes with PD-L1 at the plasma membrane and recycling endosomes, where it stabilizes PD-L1 and prevents proteasomal degradation [14]. Canagliflozin disrupted this interaction, promoting PD-L1 ubiquitination via the Cullin3–speckle-type POZ protein (SPOP) E3 ligase complex and enhancing degradation [14]. Functionally, this reduced PD-L1 expression on tumor cells and augmented cytotoxic T-cell activity in both syngeneic and humanized mouse models [14]. Notably, in these syngeneic mouse models, canagliflozin induced tumor regression to a degree similar to that observed with anti-programmed cell death protein 1 (PD-1) antibody treatment in this specific experimental setting. Thus, SGLT2 inhibition could function as a small-molecule immune checkpoint modulator, although further validation is required to determine if this potency translates to other models or clinical scenarios.

In osteosarcoma, SGLT2 inhibition activated the STING–IRF3–IFN-β pathway, enhancing infiltration of CD8-positive cytotoxic T-cells and natural killer cells in a mouse model [15]. Combination of an SGLT2 inhibitor with a STING agonist (2′-3′-cyclic GMP-AMP) produced synergistic antitumor activity [15], highlighting the ability of SGLT2 inhibition to prime the tumor microenvironment for immune-based therapies. However, as these immune-modulatory effects have primarily been observed in murine models, their clinical relevance in human tumor microenvironments remains to be confirmed. Importantly, these immune effects appear independent of systemic glycemic control, reinforcing the concept that SGLT2 inhibitors exert context-specific, non-metabolic effects in tumor biology.

Additional mechanisms and effects on the tumor microenvironment

Beyond glucose uptake, mitochondrial modulation, and immune regulation, SGLT2 inhibitors engage additional anticancer mechanisms. In breast cancer, they alter lipid metabolism, reduce inflammatory cytokine production, and enhance the cytotoxic effects of chemotherapy agents such as doxorubicin [27]. Notably, SGLT2 inhibitors may overcome multidrug resistance through direct drug–drug interactions at the cellular level. Zhong et al. [28] have demonstrated that canagliflozin functions as a potent chemosensitizer by inhibiting P-glycoprotein, an ATP-dependent efflux pump responsible for expelling chemotherapeutic agents from cells. By depleting intracellular ATP and suppressing cytoprotective autophagy (via unc-51 like autophagy activating kinase 1 [ULK1] phosphorylation), canagliflozin significantly increased the intracellular accumulation and cytotoxicity of doxorubicin in resistant human hepatocellular (adriamycin-resistant human hepatocellular carcinoma cell line [HepG2-ADR]) and breast (MCF-7) cancer cell lines [28].

In CRC cell lines, canagliflozin induces ER stress and ER-phagy, a selective form of autophagy, leading to cell death; silencing SIRT3 attenuated these effects, implicating the SGLT2–SIRT3 axis in antitumor activity [10]. In pancreatic cancer, alongside AMPK activation, preclinical studies in cell lines have reported inhibition of oncogenic PI3K/AKT and Hippo pathways [24,29], underscoring broad metabolic effects. Thyroid cancer xenograft models further support pleiotropic actions of SGLT2 inhibition, where canagliflozin reduced glucose uptake and glycolysis, suppressed AKT/mTOR signaling, and activated AMPK, while simultaneously inducing G1/S phase arrest and apoptosis through DNA damage response pathways including phosphorylated H2A histone family member X accumulation and ataxia-telangiectasia mutated/checkpoint kinase 2 signaling [30].

Moreover, in preclinical studies, dapagliflozin was shown to attenuate tumor growth in two obesity-associated cancer models, including E0771 breast cancer and MC38 colon adenocarcinoma, in vivo [26]. Notably, the antitumor effect was abrogated when hyperinsulinemia was restored by subcutaneous insulin infusion, indicating that insulin excess itself directly promotes tumor progression in the context of obesity [26]. These findings highlight hyperinsulinemia as a key driver of breast and colon cancer growth and suggest that SGLT2 inhibitors, through their glucose- and insulin-lowering properties, may represent a clinically available strategy to counteract obesity-associated tumor progression.

Collectively, these findings show that SGLT2 inhibitors act through pleiotropic mechanisms, targeting tumor metabolism, mitochondrial function, immune interactions, and tumor microenvironment (Fig. 1). While encouraging, this mechanistic diversity complicates interpretation and emphasizes the need for systematic studies to define tumor- and context-specific effects.

Integrating systemic and cell-intrinsic mechanisms

While SGLT2 inhibitors exhibit diverse anticancer properties, their mechanism of action may be context-dependent, relying on a balance between systemic metabolic modulation and cell-intrinsic effects. In obesity-associated malignancies such as breast cancer and CRC, the anticancer activity appears largely secondary to systemic improvements. SGLT2 inhibitors decrease circulating glucose and insulin levels, thereby reducing signaling through the mitogenic PI3K/AKT/mTOR axis [25,26,31]. This systemic dependency is underscored by preclinical findings where the antitumor efficacy of dapagliflozin in obese mouse models was abolished when hyperinsulinemia was restored via exogenous insulin infusion [26]. In this context, the agent functions primarily as a metabolic normalizer that reverses the tumor-promoting environment of systemic insulin resistance.

In contrast, for tumors such as pancreatic and prostate adenocarcinomas that functionally overexpress SGLT2 [8], the mechanism likely involves direct pharmacological blockade of glucose uptake and subsequent mitochondrial stress. Crucially, this direct effect does not strictly rely on reversing systemic obesity. This mechanistic distinction helps resolve apparent clinical inconsistencies, particularly the observation that individuals without obesity, who lack severe systemic metabolic dysregulation, may still experience reduced prostate cancer risk through direct transporter inhibition.

To provide a clear overview of the current evidence landscape, the specific anticancer mechanisms validated in human tissues versus those observed in preclinical models are comprehensively summarized in Table 1.

Table 1

Mechanism-based evidence for anticancer actions of SGLT2 inhibitors across human and preclinical models

Heterogeneity among SGLT2 inhibitors: class effects vs. agent-specific actions

Although SGLT2 inhibitors share a common mechanism for lowering blood glucose, they exhibit distinct pharmacokinetic and pharmacodynamic profiles that may differentially influence their anticancer potential. Current evidence suggests that their antineoplastic activities should be conceptualized as a dichotomy of ‘class effects’ versus ‘agent-specific actions.’

The reduction of systemic glucose and insulin levels represents a fundamental class effect. By reversing hyperinsulinemia, SGLT2 inhibitors potentially attenuate the activation of the PI3K/Akt/mTOR signaling pathway in cancer cells [26,31]. This shared mechanism likely provides broad therapeutic benefit in obesity-driven malignancies, such as breast cancer and CRC, independent of the specific molecule employed. In contrast, significant heterogeneity exists regarding direct cellular toxicity and target selectivity. Canagliflozin is chemically distinct, exhibiting relatively lower selectivity for SGLT2 over SGLT1 (approximately 250-fold) compared with highly selective agents like dapagliflozin (approximately 1,200-fold) or empagliflozin (approximately 2,500-fold) (Table 2) [7,32]. Furthermore, canagliflozin demonstrates more potent off-target inhibition of mitochondrial complex I and glutamate dehydrogenase at micromolar concentrations, a property that is less pronounced in the more selective inhibitors (Table 2) [7,23,33].

Table 2

Comparative heterogeneity of SGLT2 inhibitors in oncology: selectivity, potency, and mechanisms

This heterogeneity is particularly relevant in the context of SGLT1, which is frequently expressed in malignancies such as ovarian, prostate and pancreatic cancers [8,34]. In these tumors, SGLT1 may serve as a metabolic salvage pathway to maintain glucose uptake when GLUT transporters are insufficient. Consequently, canagliflozin’s ability to inhibit SGLT1 at achievable intestinal or intratumoral concentrations may offer a therapeutic advantage in SGLT1-high tumors that ‘cleaner,’ more selective SGLT2 inhibitors might miss [7,32]. However, it is important to emphasize that while high drug concentrations are achieved locally in the gastrointestinal tract, systemic plasma levels are generally much lower. Therefore, whether canagliflozin can reach sufficient concentrations to inhibit SGLT1 or mitochondrial complex I in distant organs like the prostate or pancreas remains pharmacokinetically uncertain. Thus, while agents such as empagliflozin effectively target systemic metabolic drivers, canagliflozin may theoretically function as a broader ‘dual inhibitor’ of tumor bioenergetics.

Prostate cancer

Prostate cancer has been extensively investigated in relation to SGLT2 inhibition. Functional SGLT2 expression has been confirmed in xenograft models, where Me4FDG uptake demonstrated active SGLT2-mediated glucose transport [8]. Pharmacologic inhibition with canagliflozin markedly reduced tumor growth in PC3 xenografts, accompanied by lower cellular ATP levels and activation of AMPK signaling in human prostate cancer cell lines [13]; canagliflozin also enhanced the efficacy of radiotherapy (RT) by sensitizing prostate cancer cells to ionizing radiation [13]. This radiosensitization was linked to AMPK phosphorylation, suppression of mTOR/MAPK signaling, and apoptosis, producing stronger tumor regression in xenograft models [13]. A drug-target Mendelian randomization (MR) study further implicated circulating metabolites regulated by SGLT2 inhibition as potential mediators of reduced prostate cancer progression [35].

These findings suggest that SGLT2 inhibitors may be especially effective in metabolically aggressive or treatment-resistant prostate cancers and could serve as adjuvant agents to improve RT outcomes. Translationally, prostate cancer represents one of the most promising indications for clinical development of SGLT2 inhibitors.

Pancreatic cancer

PDAC is characterized by marked glucose dependence and poor prognosis. Functional expression of SGLT1 and SGLT2 has been demonstrated in human pancreatic tumor tissues, with Me4FDG-PET imaging enabling in vivo visualization of glucose uptake [8]. In xenograft models, canagliflozin significantly suppressed tumor growth, reducing proliferation markers and impairing glucose utilization [8]. Mechanistic studies in cell lines further revealed that canagliflozin downregulates GLUT1 and LDHA via PI3K/AKT/mTOR suppression, thereby inhibiting glycolysis [24]. However, direct clinical validation of these metabolic alterations in patients remains to be established.

Combination strategies have also been explored. A clinical feasibility study showed that dapagliflozin combined with standard chemotherapy was tolerable in advanced pancreatic adenocarcinoma, with signs of improved metabolic profiles and possible therapeutic synergy [36]. Although preliminary, these results suggest that incorporating SGLT2 inhibitors into multimodal pancreatic cancer regimens may enhance sensitivity to cytotoxic therapy by imposing metabolic stress.

Breast cancer

Preclinical studies also support SGLT2 inhibition in breast cancer. In human breast cancer MCF-7 cell lines, ipragliflozin inhibited their proliferation in a dose-dependent manner, an effect abolished by SGLT2 knockdown, confirming specificity [21]. Mechanistically, this was associated with membrane hyperpolarization, reduced sodium/glucose cotransport, and mitochondrial destabilization, leading to growth arrest.

Broader studies demonstrated that canagliflozin, dapagliflozin, and empagliflozin activate AMPK, suppress mTOR signaling, induce apoptosis, and modulate lipid and inflammatory pathways in various breast cancer cell lines [27,37]. Synergistic effects have been observed when combined with doxorubicin, RT, or PI3K inhibitors, particularly in triple-negative breast cancer (TNBC) models, which are highly treatment resistant [38]. Notably, SGLT2 inhibition also reduced doxorubicin-associated cardiotoxicity [39–41], suggesting dual benefit in oncology. While promising, most mechanistic data in breast cancer currently rely on cell culture models, warranting further validation in patient-derived xenografts or clinical tissue samples.

Colorectal cancer

Human CRC cell lines (HCT116, HT-29) express functional SGLT2, and inhibition with canagliflozin disrupts metabolic homeostasis [10]. In these in vitro models, treatment caused cell-cycle arrest, impaired mitochondrial respiration, increased ER stress, and induction of ER-phagy [10]. These effects were mediated by SIRT3 upregulation, a mitochondrial deacetylase regulating energy metabolism and oxidative stress [10]. Silencing SIRT3 attenuated cytotoxicity, confirming its role as a downstream effector.

These data highlight the SGLT2–SIRT3 axis as a novel pathway in CRC biology. By targeting mitochondrial dysfunction and ER stress, SGLT2 inhibitors may offer a therapeutic approach distinct from conventional cytotoxic or targeted agents. However, the lack of in vivo validation in this context limits the immediate translational applicability of these specific mechanistic findings.

Hepatocellular carcinoma

Given the link between diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and HCC, SGLT2 inhibitors are positioned to intervene in hepatocarcinogenesis. In a streptozotocin-induced nonalcoholic steatohepatitis (NASH)-HCC mouse model, canagliflozin significantly reduced hepatic tumors and suppressed markers such as α-fetoprotein via anti-steatotic effects, G1 cell-cycle arrest, and caspase-3 activation [42]. Rao et al. [20] have recently reported that empagliflozin and canagliflozin delayed c-Myc-induced HCC progression in mice by directly binding to mTOR, inhibiting downstream signaling, and suppressing ATP production in c-Myc-overexpressing hepatocytes. Elevated SGLT2 expression was confirmed in both mouse models and human HCC tissues via IHC, suggesting a potential for direct SGLT2-mediated inhibition [20,42,43].

Real-world evidence supports a protective effect, particularly in high-risk populations. A multinational TriNetX cohort study (n=187,860) has reported a 57% lower HCC risk (adjusted hazards ratio [HR], 0.43) in SGLT2 inhibitor users with MASLD and T2DM compared to active comparators [44]. Similarly, a Hong Kong study has indicated a 58% risk reduction versus dipeptidyl peptidase-4 (DPP-4) inhibitors, a benefit persisting in patients with chronic viral hepatitis and cirrhosis [45]. While a Korean nationwide study identified neutral effects in the general non-alcoholic fatty liver disease population, significant protection was observed in high-risk patients with concomitant T2DM, fatty liver, and chronic viral hepatitis [46]. Thus, SGLT2 inhibitors may modify disease trajectory in livers primed by metabolic or viral insults.

Lung cancer

Non-small cell lung cancer (NSCLC) represents a promising target for combination strategies. Canagliflozin has been shown to inhibit tumor growth in human NSCLC xenografts and synergize with RT [47]. Mechanistically, canagliflozin enhances RT efficacy in NSCLC cell lines by blocking mitochondrial complex I and activating AMPK, which suppresses the mTOR–hypoxia-inducible factor 1-alpha (HIF-1α) axis and downregulates histone deacetylase 2 [47]. This metabolic stress renders hypoxic, radioresistant tumor cells more vulnerable to DNA damage. Importantly, SGLT2 expression has been detected in human lung cancer tissues via IHC [48], supporting the clinical relevance of these findings.

In contrast to preclinical data, clinical evidence remains nascent. A UK population-based cohort study identified no association with short-term lung cancer risk (HR, 0.96) with the use of SGLT2 inhibitors compared to DPP-4 inhibitors over a median 2.4-year follow-up [49]. This neutral finding may reflect the short latency period analyzed; although SGLT2 inhibitors show promise as radiosensitizers in established disease, their potential role in primary prevention requires longer observation to confirm.

Osteosarcoma and other malignancies

In osteosarcoma, a rare but aggressive bone malignancy, SGLT2 is overexpressed at the protein level [15]. Pharmacological inhibition suppressed tumor growth in vivo and increased infiltration of cytotoxic immune cells [15]. Mechanistic studies revealed activation of the STING–IRF3–IFN-β pathway, linking metabolic inhibition to innate immune activation [15]. Combination treatment with a STING agonist (2′3′-cGAMP) produced synergistic suppression, suggesting an immunometabolic strategy for treatment-resistant disease [15].

Exploratory studies have also reported antitumor effects in cervical cancer cell lines and xenografts [50], lung cancer cell lines [48], and glioblastoma cell lines and syngeneic mouse models [51]. Although preliminary, these findings suggest that SGLT2 activity extends across multiple tumor types, underscoring the broad potential of this drug class in oncology.

Findings from randomized controlled trials and meta-analyses

Evidence regarding the relationship between SGLT2 inhibitors and cancer risk largely originates from randomized controlled trials (RCTs) conducted for cardiovascular and renal outcomes (Table 3). Although not designed to assess cancer as a primary endpoint, their large sample sizes and extended follow-up provide meaningful safety data. A systematic review and meta-analysis, including 34,569 individuals with T2DM from 46 independent RCTs reported no significant association between SGLT2 inhibitor therapy and overall cancer incidence [52]. Similarly, an updated meta-analysis encompassing 76 randomized trials and more than 100,000 participants demonstrated neutral effects on cancer risk, with no increase observed for risk of cancer and cancer mortality [53]. Collectively, these data support the oncologic safety of SGLT2 inhibitors. Nonetheless, the relatively small number of cancer cases, median follow-up of approximately 3–4 years, and absence of standardized adjudication of endpoints highlight the need for longer-term oncology-focused studies.

Table 3

Clinical evidence summary of SGLT2 inhibitors and cancer outcomes

Observational cohort studies on cancer risk and outcomes

Observational analyses and nationwide cohort studies have provided additional insights into potential anticancer effects. We have demonstrated that new users of SGLT2 inhibitors exhibited a significantly lower risk of incident pancreatic cancer compared with patients initiating other glucose-lowering therapies, with consistent findings across multiple sensitivity analyses [16]. In this Korean nationwide population-based cohort study, we examined whether initiation of SGLT2 inhibitors is associated with a reduced risk of gastrointestinal malignancies in patients with T2DM, using an active-comparator, new-user design with detailed propensity-score matching (PSM). Our analysis demonstrated that SGLT2 inhibitor use was significantly associated with a lower incidence of pancreatic cancer, corresponding to an adjusted HR of 0.72 (95% confidence interval [CI], 0.55 to 0.95).

More recently, we also have reported that SGLT2 inhibitor initiation was associated with a reduced risk of prostate cancer in a similar PSM matched cohort, independent of glycemic control, or other metabolic confounders [17]. Notably, this protective association was particularly evident in non-obese individuals, as the risk reduction was more pronounced in those with a BMI <25 kg/m² (HR, 0.63; 95% CI, 0.46 to 0.86) [17]. This finding contrasts with the hypothesis that SGLT2 inhibitors act solely by counteracting obesity-driven tumor progression. Instead, it suggests that in prostate cancer—a tumor type with documented functional SGLT2 expression—the mechanism may be predominantly cell-intrinsic or driven by direct transporter inhibition. In individuals without obesity, the absence of severe systemic inflammation and insulin resistance may allow these direct cell-intrinsic effects to manifest more potently than in individuals with obesity, in whom the overwhelming systemic metabolic dysregulation could mask the drug’s direct antitumor efficacy. Thus, for prostate cancer, the benefit appears independent of the ‘anti-obesity’ effect required in other malignancies.

A notable feature of these findings is the relatively early divergence in cancer incidence rates between treatment groups. Considering the multi-step nature of carcinogenesis, which typically spans years or even decades, pharmacological intervention preventing the de novo initiation of malignant transformation within such a short timeframe is biologically implausible. Instead, this early separation likely reflects the suppression of tumor promotion and progression affecting pre-existing, subclinical lesions. In tumors expressing functional SGLT2, such as pancreatic and prostate cancer [8], the inhibitor likely acts by inducing an acute intracellular energy crisis. Direct blockade of glucose entry triggers immediate metabolic stress [8], leading to the rapid activation of AMPK and the downstream inhibition of the oncogenic mTOR pathway [22,54]. This mechanism operates locally within the tumor cells, exerting an immediate cytostatic effect independent of systemic metabolic alterations. Consequently, the growth rate of these occult microtumors might be actively suppressed, delaying their transition to clinically detectable disease and resulting in an apparent reduction in cancer incidence that manifests early in the observational period. However, this pattern might not be universal. For instance, despite the aggressive nature of NSCLC, clinical studies report neutral effects [49]. This discrepancy suggests that suppression of progression relies on functional SGLT2 overexpression. In prostate and pancreatic cancers, the drug targets a specific metabolic dependency; conversely, in tumors lacking this reliance, SGLT2 inhibition alone appears insufficient to alter the natural history, regardless of the tumor’s inherent growth rate.

Complementing these results, a recent population-based cohort study from Hong Kong directly compared prostate cancer incidence between SGLT2 inhibitor and DPP-4 inhibitor users among 42,129 male patients with T2DM. Over a median follow-up of 5.6 years, SGLT2 inhibitor users had a 55% lower risk of developing prostate cancer compared with DPP-4 inhibitor users (HR, 0.45; 95% CI, 0.30 to 0.70) [55]. Other large-scale real-world studies also suggest potential organ-specific benefits. A 2024 nationwide analysis from Japan using PSM reported no increased risk of overall cancer; the result suggested the potential advantage of SGLT2i over D DPP-4 inhibitor in reducing the development of cancer, particularly CRC [56]. Another systematic review of cohort studies found a neutral to favorable association, particularly reductions in liver (risk ratio [RR], 0.76), lung (RR, 0.87), and prostate (RR, 0.75) cancers with SGLT2 inhibitor use, compared to DPP-4 inhibitor [57]. Although residual confounding cannot be excluded, the consistency between epidemiological data and mechanistic hypotheses strengthens the plausibility of these associations.

Genetic and Mendelian randomization studies examining causality

MR analyses have further evaluated potential causal links. A drug-target MR study integrating circulating metabolites and genetic proxies for SGLT2 inhibition found genetically proxied inhibition was associated with reduced prostate cancer risk [35]. These results align with both mechanistic data and epidemiologic findings, providing genetic support for a protective effect. Although subject to assumptions inherent to MR, these approaches reduce the likelihood that observed associations are solely due to confounding. However, MR provides only indirect genetic support and cannot substitute for interventional evidence. Therefore, these findings should be interpreted as hypothesis-generating rather than definitive proof of causality.

Early translational and pilot clinical studies

Pilot studies have begun to explore SGLT2 inhibitors in oncology. A phase II trial reported that adding dapagliflozin to standard chemotherapy in patients with advanced pancreatic adenocarcinoma was well tolerated, without unexpected toxicities [36]. Notably, dapagliflozin did not exacerbate chemotherapy-related adverse events and showed favorable metabolic modulation, suggesting possible therapeutic synergy [36]. Retrospective real-world analyses indicate that concurrent use of SGLT2 inhibitors in patients with gastrointestinal cancers receiving chemotherapy or RT is associated with improved overall survival, fewer hospitalizations, and reduced treatment-related complications, without emerging safety concerns. These findings support the notion that by attenuating hyperglycemia, hyperinsulinemia, and therapy-induced metabolic stress, SGLT2 inhibitors may improve treatment tolerability and enhance host resilience in oncologic populations [58].

Although preliminary and underpowered to evaluate survival, these studies demonstrate that SGLT2 inhibitors can be safely administered to oncology patients and may complement established therapies.

Prevention of cancer therapy-related cardiotoxicity

Significant recent studies have focused on the potential of SGLT2 inhibitors to preserve cardiac function during cardiotoxic anticancer therapy. In a translational pig model of anthracycline-induced cardiotoxicity, Medina-Hernandez et al. [40] have demonstrated that empagliflozin (20 mg) prevents doxorubicin-induced left ventricular dysfunction, mitochondrial fragmentation, and energetic failure. This protection was driven by a metabolic switch favoring myocardial ketone body consumption, which provides an energy-efficient fuel source during stress [40]. However, the therapeutic scope appears to extend beyond metabolic reprogramming; accumulating preclinical evidence suggests a multifactorial protective mechanism involving the mitigation of oxidative stress, suppression of the nod-like receptor protein 3 (NLRP3) inflammasome, and inhibition of ferroptosis, alongside the restoration of autophagic flux [59].

These preclinical findings are supported by emerging clinical evidence. A recent systematic review and meta-analysis of 82,654 patients with diabetes and cancer has reported that compared to non-users, SGLT2 inhibitor users had a 54% lower risk of all-cause mortality (RR, 0.46) and a 51% reduction in heart failure hospitalization [60]. Importantly, these benefits were consistent in subgroups of patients receiving anthracycline chemotherapy, suggesting that SGLT2 inhibitors may mitigate the cardiotoxic sequelae of standard oncologic regimens [61]. Beyond anthracyclines, preclinical evidence also suggests that empagliflozin may mitigate cardiotoxicity induced by tyrosine kinase inhibitors such as sunitinib by restoring autophagic flux and activating AMPK signaling, thereby broadening the potential scope of cardioprotection in oncology [62].

Safety considerations for SGLT2 inhibitors in patients with cancer

The established safety profile of SGLT2 inhibitors in diabetes and cardiovascular disease may not fully extend to oncology. Euglycemic diabetic ketoacidosis (eDKA) is a recognized complication and may be more likely in patients with reduced oral intake, cachexia, or high catabolic states induced by chemotherapy or RT [63,64]. Volume depletion, electrolyte imbalances, and unintended weight loss may also carry greater risk in cancer populations where sarcopenia and malnutrition are common. Furthermore, specific drug–drug interactions warrant caution, particularly given the emerging interest in combining SGLT2 inhibitors with immunotherapy. Immune checkpoint inhibitors (ICIs) precipitate immune-related adverse events, including the rapid onset of autoimmune insulin-dependent diabetes (type 1 diabetes mellitus) [65]. The concurrent use of SGLT2 inhibitors in this setting poses a significant safety challenges; SGLT2 inhibition may mask the severe hyperglycemia typically heralding ICI-induced diabetes, potentially leading to a delayed diagnosis of insulin deficiency. Consequently, this combination carries a heightened risk of fulminant eDKA. Clinicians must exercise extreme vigilance, incorporate routine monitoring of blood glucose and ketones, and educate patients on eDKA symptoms, even in the absence of marked hyperglycemia. These issues underscore the importance of cautious patient selection, dose optimization, and rigorous safety monitoring in oncology-focused trials.

Summary of clinical evidence

Overall, current evidence indicates that SGLT2 inhibitors are oncologically safe and may offer protection against certain cancers. RCTs and meta-analyses consistently show neutral effects on overall cancer risk [52,53], while observational studies suggest reduced risks of pancreatic and prostate cancers [16,17]. Genetic data from MR analyses strengthen the case for a causal link, particularly in prostate cancer [35]. Early translational studies further demonstrate feasibility of combining SGLT2 inhibitors with chemotherapy, with potential benefits in metabolically aggressive tumors such as pancreatic cancer [36].

However, the current clinical evidence is largely limited to epidemiological associations. While MR studies provide supportive genetic data, they do not establish causality. Definitive prospective interventional studies specifically designed to test anticancer efficacy are currently lacking but are essential to confirm these findings. Convergence of trial, observational, genetic, and translational evidence provides a compelling rationale for further clinical investigation. Future studies incorporating biomarker-guided patient selection, longer follow-up, and oncology-specific safety monitoring are warranted to fully define the anticancer potential of SGLT2 inhibitors.

Patient selection: identifying individuals most likely to benefit from SGLT2-based anticancer approaches

Identifying the appropriate patient population is central to clinical translation of SGLT2 inhibitors in oncology (Fig. 2). The anticancer effects of SGLT2 inhibitors appear highly tumor-dependent. Preclinical studies show that tumors expressing functional SGLT2 respond more strongly to pharmacological inhibition; SGLT2 inhibitors have shown anticancer effects in prostate, pancreatic, breast, colorectal, and osteosarcoma, but less consistent responses in other cancers. Even within breast cancer, triple-negative subtypes appear more sensitive to SGLT2 inhibition, particularly when combined with chemotherapy or PI3K inhibitors [38]. This variability highlights the importance of biomarker-driven approaches, although a single biomarker strategy is likely insufficient given the drug’s dual mechanism. Detecting functional SGLT2 expression via IHC or Me4FDG-PET imaging is logical for tumors driven by direct transporter activity (e.g., prostate or pancreatic cancer); however, this approach has limitations. Relying solely on SGLT2 expression risks excluding patients who might benefit from the drug’s systemic or immunomodulatory effects, which function independently of tumor SGLT2 levels.

Fig. 2

Clinical translation framework for sodium-glucose cotransporter 2 (SGLT2) inhibitors in oncology: Who, when, and how. The potential clinical application of SGLT2 inhibitors in oncology can be structured into three domains. Patient selection (Who): functional SGLT2 expression and tumor type (prostate, pancreatic, breast, colorectal, osteosarcoma), with supportive tools such as α-methyl-4-deoxy-4-[^18F]fluoro-D-glucopyranoside positron emission tomography (Me4FDG-PET) imaging and genetic or metabolomic profiling. Timing of intervention (When): possible use in cancer prevention, as radiosensitizers, or as adjuvants to chemotherapy. Practical considerations (How): include clarifying dose–response relationships for anticancer effects, ensuring safety in oncologic patients, and conducting adequately powered clinical trials.

Consequently, future clinical trial designs should adopt a multidimensional biomarker strategy. This would ideally integrate tumor-intrinsic markers, such as SGLT2 protein expression or Me4FDG uptake, to identify malignancies susceptible to direct metabolic blockade, alongside systemic metabolic markers such as fasting insulin or C-peptide levels. The latter would help identify patients with hyperinsulinemia for whom systemic metabolic normalization is the primary therapeutic driver. Furthermore, given the emerging data on immune checkpoint modulation, incorporating immune markers such as baseline PD-L1 status or interferon gene signatures could refine the selection of candidates for combined immunotherapeutic approaches. Ultimately, critical evaluation of these composite biomarkers is essential to delineate whether the therapeutic target in a specific patient is the tumor transporter, the host metabolism, or a synergistic combination of both.

Timing of intervention: appropriate clinical contexts for SGLT2 inhibitor use

Preclinical findings suggest SGLT2 inhibitors may be particularly effective in adjuvant or neoadjuvant settings, where metabolic suppression could reduce incidence in cancers such as prostate or pancreatic cancer. In prostate cancer, canagliflozin sensitized cells to RT through AMPK activation and mTOR/MAPK inhibition, supporting its use as a radiosensitizer [13].

Synergy with immunotherapies is also promising. Canagliflozin-induced PD-L1 degradation enhanced T-cell–mediated cytotoxicity [14], while osteosarcoma models showed improved antitumor responses when SGLT2 inhibition was combined with STING agonists [15]. Translational clinical evidence further indicates that dapagliflozin can be safely combined with chemotherapy in pancreatic cancer, with favorable metabolic effects and no unexpected toxicity [36]. These findings highlight multiple potential therapeutic windows, including perioperative use, RT combinations, immunotherapy combinations, and chemotherapy combinations. However, the integration of SGLT2 inhibitors into the perioperative setting requires strict safety protocols. To prevent eDKA, clinical guidelines mandate the discontinuation of these agents 3 to 4 days prior to surgery and during periods of fasting or significant catabolic stress. Therefore, any perioperative strategy must incorporate this mandatory washout period, ensuring that the drug is withheld during the immediate surgical window while potentially being utilized in the broader neoadjuvant or adjuvant phases.

Practical considerations for integrating SGLT2 inhibitors into oncology practice

The use of SGLT2 inhibitors in oncology poses several challenges. First, the dose–response relationship requires rigorous evaluation to distinguish between on-target and off-target effects. As several direct cytotoxic effects observed in vitro occur at supra-pharmacological concentrations [23], clinical trials must assess whether standard antidiabetic dosing is sufficient to trigger anticancer activity. If the primary mechanism is systemic (e.g., lowering insulin and glucose), standard doses may suffice. However, if the mechanism relies on direct tumor SGLT2 inhibition or mitochondrial disruption, quantifying intratumoral drug concentrations via biopsy or imaging is essential to confirm whether therapeutic thresholds are met. Future studies should prioritize determining whether ‘high-dose’ strategies are safe or necessary in oncology, or if the standard ‘metabolic’ dose provides sufficient indirect benefit.

Second, safety monitoring requires adaptation. Oncology patients may face higher risks of euglycemic ketoacidosis, dehydration, electrolyte imbalance, and unintended weight loss, particularly in those with cachexia or undergoing cytotoxic therapy. Specifically, cytotoxic chemotherapy frequently induces nausea, vomiting, and poor oral intake. In these scenarios, continuous SGLT2 inhibition could precipitate acute kidney injury or euglycemic ketoacidosis. Therefore, enthusiasm for combination therapy must be balanced with proactive risk management, necessitating an intermittent dosing strategy where the drug is temporarily withheld during the nadir of chemotherapy tolerability or periods of compromised oral intake. Rigorous monitoring and supportive care protocols will be essential in clinical trials.

Third, trial design should incorporate biomarker-based enrichment and translational endpoints. Me4FDG-PET or IHC can identify tumors with SGLT2 activity, while circulating metabolites, PD-L1 expression, and interferon-response genes may serve as pharmacodynamic biomarkers. Endpoints should extend beyond survival to include metabolic response, immune activation, and quality of life.

Summary of key considerations for clinical translation

Successful clinical translation of SGLT2 inhibitors will depend on three principles: selecting patients with functional SGLT2 expression or favorable immunometabolic profiles, identifying optimal timing of therapy (perioperative or in combination with RT, chemotherapy, or immunotherapy), and implementing treatment with appropriate dosing, safety monitoring, and biomarker-guided design (Fig. 2). Although evidence from preclinical, observational, and early translational studies provides a strong foundation, oncology-focused trials are essential to establish the clinical utility of SGLT2 inhibitors.