Abstract
Graphical abstract
Abstract
Although a century has passed since Otto Warburg’s discovery of the glycolytic pathway of energy production by many malignant tumors compared to normal tissues, current data cast doubt on the universality of this hypothesis. In particular, numerous recent papers suggest that in response to chemotherapy or radiotherapy, many malignant tumors prefer to activate mitochondrial oxidative phosphorylation (OXPHOS). Moreover, data from many laboratories, including our own, show that OXPHOS and related redox proteins are preferential metabolic pathways for resistant tumors and cells, and therefore may be targeted specifically in cases of tumor relapse. This work aims to provide an overview of the use of OXPHOS inhibition as an alternative therapy approach for resistant tumors and includes a description of the confirmed key mechanisms and the results of clinical trials of OXPHOS inhibitors and possible side effects arising therefrom. We mainly discuss original papers and clinical trials published in the past 5–7 years.
Introduction
Following Otto Warburg’s discovery that, compared to many normal tissues that produce small amounts of lactate, most malignant tumors produce large amounts of lactate, and that this lactate is reduced but not eliminated even in the presence of sufficient oxygen, the hypothesis was developed that tumors tend to metabolize glucose anaerobically via glycolysis and not aerobically via oxidative phosphorylation (OXPHOS) (Warburg & Minami 1923, Warburg et al. 1927). In eukaryotic cells, OXPHOS occurs with the participation of mitochondria that absorb oxygen on an electron transport chain (ETC) assembled in respirasomes, which ultimately contributes to the production of ATP (Lapuente-Brun et al. 2013). While the Warburg effect does work, and even the positron emission tomography method was invented based on it, many exceptions have been discovered recently. In particular, Warburg’s hypothesis that malignancy is associated with mitochondrial dysfunction (MDF) (Warburg 1956) does not seem to hold true, and numerous papers show that in many types of cancer, mitochondria are functional (Wallace 2012, Grasso et al. 2020, Wang et al. 2023b ). There have also been a number of publications attempting to substantiate the paradox of how rapidly dividing cancer cells manage to replenish energy expenditure in the form of ATP using only glycolysis, whereas mitochondria-mediated OXPHOS provides an order of magnitude more energy (DeBerardinis & Chandel 2020). It has been suggested that the kinetics of glycolysis, although yielding only a couple of ATPs per glucose molecule through the pyruvate cycle, is much faster than OXPHOS, which under ideal conditions can yield up to 36–38 ATPs, but takes a relatively long time (Vander Heiden et al. 2009). However, in the past decade, more and more evidence against the unambiguous interpretation of such an effect has begun to accumulate. In particular, our recent studies summarize the results of dozens of studies diverging from the Warburg effect ((Uslu et al. 2024, Uslu et al. 2025). Moreover, the emergence of publicly available data on full-length gene expression in cancer patients has made it possible to show an inverse correlation of OXPHOS gene expression with 5-year survival of patients in different types of cancer. Other studies have shown an increased role for redox pathways and, in particular, OXPHOS in resistant tumor types and in cancer stem cells (CSCs), a subset of cancer cells with stem-like qualities (Lu et al. 2015, Lleonart et al. 2018, Luo et al. 2018, Abad et al. 2019, 2020, Rai et al. 2025). These and other data on the expression of key proteins of mitochondrial respiratory complexes I–V, involved in OXPHOS, in less aggressive forms of cancer have prompted consideration of the OXPHOS axis as a potential target for the treatment of specific forms of malignant tumors, particularly recurrent, highly metastatic, and sensitive to radio- and chemotherapy (Lyakhovich & Graifer 2015, Lleonart et al. 2017, Abad et al. 2019, Karp & Lyakhovich 2022).
In this paper, we present an overview of the use of OXPHOS inhibition as an alternative therapy for resistant tumors, describing several confirmed key mechanisms and the results of clinical trials of OXPHOS inhibitors and possible side effects arising therefrom. Original works published in the past decade are mainly reviewed.
Mechanisms underlying OXPHOS-driven cancer resistance
Despite the stereotype dominating since the Warburg hypothesis, in recent years, more and more data have been accumulated, which show that in case of radio- or chemo-resistant malignant tumors, the corresponding cells use not glycolysis but OXPHOS to enhance their survival and adapt to therapeutic pressures (Sica et al. 2020). To show the relationship between OXPHOS and malignant tumor resistances below, we outline several interrelated mechanisms.
Increased mitochondrial biogenesis and activity through PGC1α upregulation
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a key transcriptional coactivator that regulates mitochondrial biogenesis, OXPHOS, and energy metabolism in most cell types (Qian et al. 2024). It integrates cellular signals to adapt mitochondrial function during metabolic stress, promoting energy homeostasis and survival (LeBleu et al. 2014). PGC1α is often elevated in resistant lung cancer cells, enhancing mitochondrial activity and ATP production (Feng et al. 2023). Another study on cisplatin-resistant H1299 and H460 lung cancer cells showed a consistent increase in PGC-1α expression accompanied by enhanced OXPHOS function (Cruz-Bermúdez et al. 2019). Similarly, its elevated expression in colorectal cancer cells promotes a stem cell-like phenotype: self-renewal and ability to form tumorspheres and resistance to chemotherapy such as oxaliplatin and 5-FU (Alcalá et al. 2020, Deng et al. 2023). In vitro expression of PGC1α is upregulated in breast CSCs, supporting stemness and promoting cancer relapse (Liu et al. 2020). These data suggest that PGC1α may regulate mitochondrial adaptation, linking metabolic plasticity to drug resistance and cancer stemness, and therefore serve as a potential target for suppressing resistant cancer cells (Raggi et al. 2021).
Hypoxia-induced OXPHOS activation via HIF-1α
Often overexpression of PGC-1α leads to increased expression of genes regulated by dimeric hypoxia-inducible factor (HIF-1α), which plays a critical role in tumor resistance by promoting a metabolic shift toward glycolysis under hypoxic conditions, bypassing mitochondrial OXPHOS (de Heer et al. 2020). HIF-1α has also been linked to the regulation of OXPHOS in cancer-resistant cells (Bao et al. 2021). Recent findings reveal that HIF-1α can indirectly enhance mitochondrial function by via miR-210-3p that interferes with OXPHOS regulators (Pranzini et al. 2019). Conversely, suppressing miR-210-3p has been demonstrated to promote OXPHOS activity, thus contributing to resistance mechanisms (Rytelewski et al. 2020). HIF-1α-mediated signaling helps cancer cells regulate both glycolysis and OXPHOS in response to external and intracellular signals (Andreucci et al. 2018). In resistant cells, HIF-1α stabilizes and directly translocates to mitochondria, where it inhibits ROS production and prevents apoptosis. It achieves this by reducing complex I activity in the ETC and activating autophagy through the BNIP3 protein, enhancing mitochondrial survival and function. These HIF-1α-related mechanisms contribute to cancer cell persistence and resistance (Li et al. 2019, Mudassar et al. 2020).
Alterations in mitochondrial membrane potential
It has been shown that, on average, mitochondria in cancer cells are hyperpolarized with an MMP of −220 mV compared to normal cells displaying MMP around −140 mV (Kalyanaraman et al. 2023). The formation and maintenance of MMP depends on many factors relevant to high OXPHOS dependence, including substrate influx into mitochondria, ETC activity, and ATP demand (Rovini et al. 2021). Non-small-cell lung cancer (NSCLC) cells resistant to therapy with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), the standard of care for lung cancer patients, showed increased MMP levels along with enhanced OXPHOS capacity (Lin et al. 2023). This suggests that increased MMP promoting more efficient mitochondrial function and ATP production may contribute to malignant cell resilience, thus allowing cancer cells to maintain energy homeostasis and adapt to metabolic stress. In general, mitochondrial hyperpolarization, especially in the resistant cancer phenotype, allows such cells to avoid apoptosis by inhibiting mitochondrial outer membrane permeabilization, and hence the release of pro-apoptotic molecules such as cytochrome c (Forrest 2015, Jin et al. 2022). In turn, blocking MMP allowed the resistance of cancer cells to be overcome (Lee et al. 2019).
AMPK-mTOR signaling in cancer resistance
Through its regulation of mTOR complex (mTORC1), a key regulator of cell growth and metabolism, AMP-activated protein kinase (AMPK) contributes significantly to cancer resistance (Keerthana et al. 2023). AMPK is being investigated more and more as a target to block cancer resistance mechanisms because of its function in stress adaption and survival. AMPK facilitates autophagy by blocking mTORC1, which allows cancer cells to resist stressors such as chemotherapy (Liu et al. 2014). To this end, OXPHOS and autophagy inhibition was suggested as a prerequisite to target some cancer cells with enhanced AMPK expression (Esner et al. 2017). In addition, AMPK promotes metabolic reprogramming, which enables tumor cells to alternate between oxidative phosphorylation (OXPHOS) and glycolysis in response to treatment demands (Hua et al. 2019). Furthermore, through the regulation of p53 and mTORC1, AMPK activation can result in cell cycle arrest, which lowers cancer proliferation and increases resistance to therapy (Gremke et al. 2020).
Mitochondrial calcium and resistance
Calcium (Ca2+) signaling is essential for several cellular functions, including metabolism, apoptosis, and cell division, all of which are vital for cancer initiation and progression (Roberts-Thomson et al. 2019). Tumor growth and metastasis have been linked to changes in Ca2+ homeostasis (Romito et al. 2022). In the context of acute myeloid leukemia (AML), most leukemia stem cells (LSCs) survive at the expense of OXPHOS, which is supported by BCL-2 in maintaining this metabolic state, leading to cancer resistance (de Beauchamp et al. 2022). For instance, venetoclax-resistant LSCs express elevated mitochondrial Ca2+ levels and an active OXPHOS when compared with chemo-responsive cells. Disruption of mitochondrial calcium uniporter activity reduces OXPHOS and eliminates resistant LSCs, highlighting the role of calcium signaling in maintaining OXPHOS in chemoresistant cells (Sheth et al. 2024).
Epigenetic changes and resistance
Epigenetic modifications including DNA methylation and histone acetylations become crucial both for cancer initiation and for the development of resistance to therapy (Wajapeyee & Gupta 2021). These changes may silence tumor suppressor genes or activate oncogenes, thereby promoting tumor growth and increasing resistance to treatment (Wang et al. 2023a ). For example, in ibrutinib-resistant mantle cell lymphoma (MCL) cells, overexpression of DNA methyltransferase 3A (DNMT3A) increases chemoresistance by regulating metabolic gene expression and enhancing OXPHOS activity. Mechanistically, DNMT3A increases OXPHOS by promoting MYC target gene expression through interaction with the transcription factors MEF2B and MYC, resulting in metabolic reprogramming (Hoang et al. 2024).
Mitochondrial dynamics and resistance
The fusion and fission processes that make up mitochondrial dynamics are essential for preserving cellular homeostasis and have been linked to mechanisms of cancer resistance (Genovese et al. 2021). Changes in these dynamics can affect apoptosis, energy generation, and mitochondrial function, which can lead to the development of chemoresistance in a variety of malignancies (Jin et al. 2022). In patients with AML, high IL6 levels are associated with poor treatment outcomes. On a molecular level, IL6 stimulates mitofusin 1 (MFN1), increasing mitochondrial fusion and OXPHOS, leading to chemoresistance (Larrue et al. 2023). Mouse models demonstrate that IL6-induced MFN1 expression enhances OXPHOS and tolerance to cytarabine (Ara-C). Inhibiting IL6 signaling reduces MFN1, disrupts mitochondrial fusion, and restores chemosensitivity, emphasizing mitochondrial fusion as a critical role in cancer chemoresistance (Hou et al. 2023).
NRF1 and resistance
Nuclear respiratory factor 1 (NRF1) regulates mitochondrial biogenesis and OXPHOS, two crucial aspects of cancer cell metabolism (Wang et al. 2022). NRF1’s ability to enhance mitochondrial activity may allow cancer cells to survive in hostile environments, making it a potential target for treatment strategies (Bhawe & Roy 2018). NRF1 enhances OXPHOS by increasing ATP synthesis, which promotes tumor growth, anoikis resistance, and epithelial–mesenchymal transition (EMT) in breast cancer cells (Zhou et al. 2018). Increased NRF1 expression promotes EMT by regulating ROS-detoxifying enzymes that keep ROS levels low, ensuring cell survival and promoting metastasis. This mechanism allows NRF1 to promote survival under stress conditions by facilitating tumor development and allowing cancer cells to avoid anoikis by enhancing both mitochondrial activity and antioxidant defense (Sun et al. 2023).
Clinical trials targeting OXPHOS inhibition
Because increases in OXPHOS have been reported in many types of malignancies, OXPHOS inhibition has been proposed as an alternative or adjunct to standard anticancer therapy. In this section and Fig. 1, we highlight the mechanisms of OXPHOS inhibition and the targets used as anticancer drugs. In the next subsections, we provided the most relevant data on clinical trials examining OXPHOS inhibitors in resistant or relapse malignancies and potential limitations of using these drugs in cancer treatment.
OXPHOS inhibitors are able to target resistant malignant tumors. Heterogeneity of malignant tumors seems to divide cells into glycolytically prone (corresponding to the Warburg effect) and OXPHOS-dependent population. The latter are often found in chemo- or radio-resistant tumors, and it is this subpopulation that can be targeted by OXPHOS inhibitors, preferentially aimed at suppressing mitochondrial respiratory complexes.
Citation: Redox Experimental Medicine 2025, 1; 10.1530/REM-25-0003
Commonly used OXPHOS inhibitors in cancer studies
Currently, various drugs are used as OXPHOS inhibitors, mostly targeting respiratory complexes I, II, and III (CI-III), ATP synthase, disrupting MMP, or blocking specific TCA cycle enzymes (Carter et al. 2020, Cazzoli et al. 2023, Zeng & Hu 2023, Lu et al. 2024, Udumula et al. 2024). One of the first drugs in the class of mitochondrial complex inhibitors is IACS-010759 that selectively inhibits CI activity and impairs OXPHOS (Cazzoli et al. 2023). This study shows IACS-010759-dependent depletion of ATP, ROS generation, and destabilization of cancerous inhibitor PP2A (CIP2A), leading to PP2A reactivation and suppression of oncogenic signaling that correlates with tumor aggressiveness, and ultimately induces tumor cell death via chaperone-mediated autophagy in some tumor cell lines. In ibrutinib-resistant MCL mice, targeting OXPHOS-dependent metabolic reprogramming with IACS-010759 significantly suppressed tumorigenesis. This was achieved by disrupting metabolic adaptations that allow cancer cells to survive chemotherapy (Zhang et al. 2019a ). It also slowed disease progression and increased survival in malignant ovarian tumors with high PGC1a/b expression in mice (Ghilardi et al. 2022). In lung cancer, IACS-010759 counteracted resistance to EGFR TKIs by inhibiting the IGF2BP3-COX6B2 axis both in vitro and in vivo (Lin et al. 2023).
In models of basal-like triple-negative breast cancer, it improved efficacy when paired with CDK4/6 inhibitors or multi-kinase inhibitors (Evans et al. 2021). In three-dimensional tumor cultures and mouse models, inhibition of OXPHOS with IACS-010759 was shown to induce a metabolic shift from OXPHOS to glycolysis, reducing oxygen consumption and diffusion-limited hypoxia (Boreel et al. 2024). Furthermore, in estrogen receptor-positive breast cancer, especially in endocrine-resistant and CDK4/6 inhibitor-resistant models, IACS-010759 significantly suppressed tumor development (El-Botty et al. 2023).
Metformin, an oral hypoglycemic drug approved for the treatment of type 2 diabetes, has been shown to be an antitumor agent by inhibiting mitochondrial CI, reducing ATP production and activating AMPK (Luo et al. 2021). This increases sensitivity to chemotherapy in a variety of cancers, including hepatocellular carcinoma, breast, and lung cancer (You et al. 2022). Metformin, by decreasing mitochondrial activity, increases the chemosensitivity of lung adenocarcinoma cells to pemetrexed, as indicated by reduced MMP and, in this context, decreased ATP production. Co-treatment with metformin significantly reduced cell survival compared to pemetrexed alone, indicating its potential to overcome drug resistance (Wang et al. 2024). In addition, metformin modulates tumor immunity and may be effective in the treatment of hematologic cancers, including leukemia and lymphoma (Jiang et al. 2021, Hu et al. 2023). Similarly, metformin therapy of melanoma brain metastases reversed immune suppression and increased survival through effects on OXPHOS (Fischer et al. 2021). Metformin also reduced OXPHOS and delayed tumor cell proliferation in oral squamous cell carcinoma when co-cultured with cancer-associated fibroblasts expressing integrin beta 2 (Zhang et al. 2020). In combination with other metabolic inhibitors, metformin increases therapeutic efficacy against breast cancer, hepatocellular carcinoma, cervical cancer, and lung tumor cells (Chen et al. 2024). Overall, metformin suppression of OXPHOS can be used to overcome cancer resistance and improve outcomes in various cancers.
Phenformin is another potent biguanide that affects mitochondrial CI, limiting OXPHOS and increasing ATP depletion in cancer cells (Masoud et al. 2020). It is better absorbed and has a stronger antitumor effect than metformin, but its use is limited because of the risk of fatal lactic acidosis, which leads to the accumulation of lactate in the blood and causes pH changes, especially in people with impaired liver or kidney function (Fu et al. 2022). Studies have shown that phenformin can synergize with other drugs, such as gemcitabine, in ductal pancreatic ductal adenocarcinoma (PDAC) by targeting tumors with high levels of OXPHOS (Masoud et al. 2020). Phenformin has also demonstrated antineoplastic effects in models of NSCLC, particularly in cells with metabolic alterations caused by resistance to EGFR-TKIs (Lee et al. 2019).
IM156 is a mitochondrial CI blocker that suppresses OXPHOS more potently than other biguanides (Izreig et al. 2020). It reduces cellular respiration and ATP production in a variety of cancer types, including Myc lymphoma, glioblastoma, and EGFR-mutated lung cancer. It also stimulates AMPK, which inhibits mTOR and suppresses cancer cell proliferation (Janku et al. 2022).
Rotenone is another potent inhibitor of mitochondrial CI, leading to impaired OXPHOS and ATP production (Zhao et al. 2020). It has shown therapeutic potential in AML cells by inducing metabolic reprogramming (Zhao et al. 2020). It sensitizes some chemoresistant cancer cells to drugs such as cisplatin, indicating a synergistic potential for targeting metabolic pathways (Cruz-Bermúdez et al. 2019). Inhibition of OXPHOS by rotenone in breast cancer models prevents EMT and its associated signaling pathways, suggesting a role in limiting metastasis (Hu et al. 2020). Moreover, rotenone significantly suppressed cell proliferation, migration, and mitochondrial function through the downregulation of several important OXPHOS-related proteins and increased mitochondrial ROS in colorectal carcinoma (CRC) cells (Qin et al. 2023).
Atovaquone (ATO) is an FDA-approved mitochondrial CIII inhibitor and antimalarial drug that has been shown to effectively target OXPHOS and reduce ATP in cancer cells (Lu et al. 2024). Due to its favorable safety profile, ATO has been marketed for over 30 years (Ashton et al. 2018). Atovaquone plays a dual role: i) it inhibits cytochrome bc1 complex in the ETC and thus affects ATP production; and ii) it can also promote aerobic glycolysis while suppressing ROS formation in breast cancer cells (Fiorillo et al. 2016). As a result, it was effective in reducing tumor hypoxia, enhancing tumor sensitivity to radiation and restoring drug sensitivity in breast and ovarian cancer cell lines (Beerkens et al. 2024, Lu et al. 2024). More impressively, ATO selectively targeted the CSCs and induced apoptosis with minimal impact on normal cells (Fiorillo et al. 2016). More advanced formulations such as PEGylated atovaquone and mitochondria-targeted atovaquone can increase drug chemosensitivity (Cheng et al. 2022).
ME-344, a second-generation isoflavone, inhibits mitochondrial CI and CIII (Zhang et al. 2019b ). ME-344 has been used in the treatment of AML in preclinical studies (Jeyaraju et al. 2016, Carter et al. 2020). In contrast to normal hematopoietic stem cells, which remain intact, ME344 exhibited cytotoxicity against LSCs (Hurrish et al. 2024). Mechanistically, ME-344 can interfere with tubulin polymerization and induce cell cycle arrest (Jeyaraju et al. 2016).
CPI-613 (devimistat) is a dual-acting pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase inhibitor that can also disrupt OXPHOS and the TCA cycle (Gampala et al. 2021). It induces MDF, defined by increased ROS production, loss of MMP, and onset of apoptosis (Udumula et al. 2024). So far, preclinical studies have proven its efficacy in chemoresistant lung, ovarian, and colorectal cancer models (Bellio et al. 2019, Arnold et al. 2022, Khan et al. 2023). The effect of CPI-613 can be described as mitochondrial collapse, which manifests itself as increased oxidative stress, mitochondrial membrane depolarization, cytochrome c release and apoptosis (Udumula et al. 2024).
Exploring OXPHOS inhibitors in clinical trials
Recently, many OXPHOS inhibitors were applied as a cancer treatment in a number of clinical trials (Janku et al. 2022, Karp & Lyakhovich 2022). In particular, these inhibitors have been used in aggressive and chemoresistant cancers (Mohan et al. 2023) either as monotherapeutic drugs or in conjunction with chemo- and radiotherapy or immune checkpoint inhibitors (ICIs) (Chen et al. 2020, Anderson et al. 2022, Tian et al. 2024). IACS-010759, CPI-613, IM156, and metformin are among the OXPHOS inhibitors that have advanced to clinical development in a variety of cancer types, which are summarized in Table 1.
Clinical trials using OXPHOS inhibitors in resistant cancer types.
| Drug/study phase | Period | Sample size | Types of tumors | Mode of action | Clinical outcomes | Side effects | Accession # | References |
|---|---|---|---|---|---|---|---|---|
| IACS-010759 | ||||||||
| 1 | 09/2016–04/2022 | 17 | Relapsed or refractory AML | CI inhibitor | No response in AML patients | Lung infection, lactic acidosis | NCT02882321 | Yap et al. (2023) |
| 1 | 11/2017–11/2020 | 23 | Advanced solid tumors | CI inhibitor | Partial response | Elevated blood lactate, nausea | NCT03291938 | Yap et al. (2023) |
| Metformin | ||||||||
| 2 | 01/2019–01/2021 | 20 | Resectable PDAC | CI inhibitor | NCT02978547 | |||
| 1a | 05/2018–11/2021 | 18 | Thoracic neoplasm | CI inhibitor | Diarrhea | NCT03477162 | ||
| 3 | 10/2018–09/2020 | 62 | OPMLs | CI inhibitor | NCT03685409 | |||
| 2 | 08/2012–01-2015 | 7 | CRC | CI inhibitor | NCT01632020 | |||
| ME-344 | ||||||||
| 1 | 05/2012–08/2014 | 30 | Refractory solid tumors | CI + CIII inhibitor | Well-tolerated, partial response | Neurotoxicity, neuropathy | NCT01544322 | Bendell et al. (2015) |
| IM156 | ||||||||
| 1 | 10/2017–07/2020 | 22 | Advanced solid tumors | CI inhibitor | Decrease tumor growth | Nausea, diarrhea, vomiting | NCT03272256 | Rha et al. (2020) |
| CPI-613 | ||||||||
| 1–2 | 08/2008–12/2016 | 39 | Advanced malignancies | TCA cycle inhibitor | NCT00741403 | |||
| 2 | 10/2013–12/2015 | 15 | Relapsed/refractory small cell lung cancer | TCA cycle inhibitor | No complete or partial response | NCT01931787 | Lycan et al. (2016) | |
| 2 | 06/2013–12/2016 | 7 | Advanced and/or metastatic solid tumor | TCA cycle inhibitor | NCT01832857 | Liu et al. (2023a) | ||
| 2 | 12/2018–12/2025 | 24 | Relapsed or refractory Burkitt lymphoma/leukemia or HGBL | TCA cycle inhibitor | NCT03793140 | |||
| Atovaquone | ||||||||
| 1a | 05/2016–12/2018 | 46 | Resectable NSCLC | CIII inhibitor | Induced reduction in tumor hypoxia | NCT02628080 | Bourigault et al. (2021) |
IACS-010759 was assessed in two phase 1 clinical trials in relapsed or refractory AML (NCT02882321) and advanced solid tumors (NCT03291938). In the AML trial, patients took IACS-01059 orally but revealed no response. In the solid tumor cohort, eight patients exhibited stabilization of disease, indicating that their tumors were growing slower, while one patient showed a partial response and a reduction in tumor size (Yap et al. 2023). As a result, both studies were terminated, highlighting the need for optimized therapeutic strategies.
Metformin was re-approved as an anticancer drug in a neoadjuvant study of resectable PDAC (NCT02978547). This is a phase II study in which 20 patients received metformin 500 mg twice daily for 7 or more days before surgery. Tumor and normal samples were examined histologically for markers of cell proliferation (Ki67) and apoptosis. Blood and urine were assessed for glucose, insulin, and metabolomic profiling. The study tests the effect of metformin in patients with solid tumors of breast origin and the possibility of its inclusion in preoperative treatment regimens for patients with PDAC. Another study examined the concentrations achieved in neoplastic tissues using extended-release metformin: 750 mg, then the dose was increased to twice daily for 3–6 days before surgery (NCT03477162). This study investigated the pharmacokinetics of metformin and its effect on AMPK signaling in cancer tissues. Another randomized trial was performed to identify the role of metformin in preventing malignant transformation from oral potentially malignant lesions (OPMLs), e.g., leucoplakias (NCT03685409). The most significant objective was to determine whether metformin could improve clinical prognosis and reduce the rates of malignant transformation patients with OPML. A randomized, double-blind, placebo-controlled clinical trial to evaluate the short-term effects of metformin treatment on biomarkers and signaling pathways associated with cancer development and progression revealed that while metformin treatment reduced insulin levels, tumor growth and progression remained unchanged (NCT01632020).
The ME-344 inhibitor was used in a phase I clinical trial to treat refractory solid tumors (NCT01544322). The drug was given intravenously with escalating doses with the MTD set at 10 mg/kg weekly. One patient with small-cell lung cancer developed a partial response lasting over 52 weeks, while others had stable disease. Pharmacokinetic data showed linearity without significant drug accumulation based on dose (Bendell et al. 2015).
IM156 has been studied in phase I trials in patients with solid tumors and lymphomas (NCT03272256). The drug was given at a dose of 100–1,200 mg daily or every other day. Stable disease was observed among 32% of patients, with two of them having long persistent response. The overall view is that IM156 is well-tolerated, with a safety profile that supports further trials with combinations (Janku et al. 2022).
CPI-613 has been used in the phase I/II trial in advanced malignancies, wherein targeting TCA cycle enzymes disrupts mitochondrial metabolism. When administered twice weekly, CPI-613 demonstrated safety with tolerability and potential antitumor activity (NCT00741403). CPI-613 was also used in phase II trial against relapsed/refractory small-cell lung cancer. Lack of response was noted with a median progression-free survival of 1.7 months and overall survival (OS) of 4.3 months (NCT01931787). Following combination treatment with topotecan, some patients experienced responses following administration of CPI-613. In patients with relapsed or refractory hematological malignancies, CPI613 was used in a phase I clinical trial (NCT01832857) (Liu et al. 2023a ). Another ongoing study investigating the effects of CPI-613 was conducted in patients with relapsed or refractory Burkitt lymphoma/leukemia or high-grade B-cell lymphoma (HGBL) (NCT03793140). This trial is actively recruiting, with objectives to assess overall response rate, survival outcomes, and biomarker correlations, although detailed efficacy results are pending.
Atovaquone was used in the ATOM trial to investigate the effects on tumor hypoxia in patients with resectable NSCLC (NCT02628080). In this clinical trial, PET imaging metrics showed that atovaquone significantly reduces hypoxia in both inner and outer tumor subregions, although with a greater magnitude in severe hypoxic and radiobiologically resistant regions, while sparing the non-hypoxic margin. The data suggest that atovaquone may radiosensitize malignancies in hypoxic conditions (Bourigault et al. 2021).
Combination therapy with OXPHOS inhibitors in clinical practice
From the above examples of clinical trials, it is clear that the use of OXPHOS inhibitors alone is only possible when OXPHOS levels in the neoplasia are sufficiently high. However, the heterogeneity of cancer tumors does not allow having such ‘ideal’ conditions, which underestimates the efficacy of inhibitors. Therefore, the combination of OXPHOS inhibitors with standard cancer therapies has attracted widespread attention due to their potential to improve therapeutic response and overcome drug resistance (Chen et al. 2020). Below, we discuss different combinations, focusing on clinical trials with relevant results, also summarized in Supplementary Table 1 (see section on Supplementary materials given at the end of the article).
Combination of chemotherapy and OXPHOS inhibitors
Combining chemotherapy with OXPHOS inhibitors such as metformin has generated a lot of interest due to their potential to improve effectiveness of chemotherapy for a variety of malignancies. In a trial against advanced ovarian cancer, metformin was given with carboplatin and paclitaxel, achieving the recommended phase II dose of 1,000 mg three times daily. The combination was quite safe, with metformin increasing the concentration of carboplatin in the body, meaning more platinum was present over time (Broekman et al. 2020). In another phase II trial on refractory colorectal cancer, metformin–irinotecan combination gave a disease control rate of 41%, as calculated by a median progression-free survival of 3.3 months and OS of 8.4 months with cost-effective option (Bragagnoli et al. 2021). The inclusion of metformin in neoadjuvant chemotherapy protocols for breast cancer showed overall response rate improvement and reduction of neuropathy (Barakat et al. 2022). Metformin, in patients with diffuse large B-cell lymphoma (DLBCL), improved clinical outcomes when combined with the R-CHOP chemotherapy regimen – standard chemotherapy regimen consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone – by increasing complete remission rates and improving survival (Hegazy et al. 2024). The efficacy of metformin in breast cancer patients undergoing neoadjuvant chemotherapy was mediated by the death receptors TRAIL and the CSC marker CD133, which may impact clinical outcome (Serageldin et al. 2024). In an ongoing phase I clinical trial, metformin in combination with vincristine, irinotecan, and temozolomide demonstrated early efficacy, including complete and partial remissions, in children with relapsed solid tumors and CNS tumors (Metts et al. 2023). Among patients with advanced ovarian cancer, a phase II study showed that the combination of metformin with paclitaxel and carboplatin resulted in a response rate of 86.7% with tolerable toxicity and a median progression-free survival of 21 months (Micha et al. 2023). A phase II clinical trial investigating the combination of metformin and TMZ in patients with high-grade gliomas is evaluating the addition of metformin to conventional treatment in patients with advanced prostate cancer (NCT05929495, NCT03137186). With a focus on complete pathological response, a clinical study is investigating the efficacy of metformin in combination with chemotherapy in breast cancer (NCT01566799). Finally, the combination of metformin and docetaxel in metastatic hormone-refractory prostate cancer is investigated in phase II clinical trial (NCT01796028). There has been no enhancement of the traditional docetaxel in metastatic castration-resistant prostate cancer (mCRPC) treated with metformin (Pujalte Martin et al. 2021).
In relapsed AML, devimistat demonstrated a 44% response rate in combination with high-dose chemotherapy (Anderson et al. 2022). CPI-613 demonstrated impressive activity in combination with FOLFIRINOX in metastatic pancreatic cancer, with an OS rate of 1.8 years (Mangieri et al. 2023). In advanced biliary tract cancer, the overall response rate to devimistat in combination with gemcitabine–cisplatin was 45%, with a median progression-free survival of 10 months, providing initial efficacy of this combination in patients (Mohan et al. 2023). The ARMADA 2000 trial (NCT03504410) is evaluating the use of CPI-613 (devimistat) in combination with cytarabine and mitoxantrone in older patients with relapsed or refractory AML. This phase III study showed a remission rate of 52% and a median OS of 12.4 months, highlighting the synergistic potential of devimistat with cytotoxic agents in the treatment of AML (Pardee et al. 2019). NCT00907166 is investigating the safety and efficacy of CPI-613 in combination with gemcitabine in cancer patients. Furthermore, the safety of ME-344 in combination with Hycamtin® in patients with solid tumors is currently undergoing investigation (NCT02100007). In locally advanced HER2-negative breast cancer, treatment with ME-344 after bevacizumab reduced tumor metabolic activity and proliferation, as assessed by Ki67 and SDH staining (NCT02806817) (Quintela-Fandino et al. 2020). IM156 was used in combination with gemcitabine and Nab-paclitaxel in an ongoing phase Ib study in patients with advanced PDAC (NCT05497778). The trial was designed to exploit tumor mitochondrial vulnerabilities and enhance the activity of chemotherapeutic agents (results pending). Finally, the OXPHOS CI inhibitor OPB-111077 demonstrated synergistic antitumor activity with bendamustine and rituximab in recurrent DLBCL and is currently being studied for broader therapeutic use (Takaki & Ohi 2024).
Combination of radiotherapy and OXPHOS inhibitors
Radiotherapy in combination with OXPHOS inhibitors is a promising approach to improve the efficacy of cancer treatment, especially in tumors with high metabolic demands (Boreel et al. 2021). In a clinical trial aiming to target OXPHOS-dependent malignancies, metformin with radiation therapy reduced tumor growth in glioblastoma by more than 50% (NCT04945148). By lowering tumor hypoxia, metformin, when used as an adjuvant to radiochemotherapy, has the potential to improve survival and reduce treatment-related morbidity in advanced NSCLC (NCT02109549). The combination of metformin and radiotherapy used in a trial of recurrent brain tumors targeting glucose-dependent tumor cells; tumor control was achieved (NCT02149459). According to the PET scan study (NCT02285855) metformin raised metabolic activity in most NSCLC tumors, indicating a complicated metabolic reaction (Chun et al. 2020). There was no additional clinical benefit for patients with stage III unresectable NSCLC when metformin was given in combination with chemoradiation, according to the NRG-LU001 trial (Skinner et al. 2021). When used in combination with chemoradiation, the CPI-613 inhibitor is expected to demonstrate safety and potential to improve local tumor control in PDAC; the study is still ongoing and was found to be safe and tolerable, indicating the need for further optimization (NCT05325281) (Kamgar et al. 2024).
Combination of immunotherapy and OXPHOS inhibitors
Combination therapy using OXPHOS inhibitors and immunotherapies has shown potential in combating cancer resistance (Cadassou & Jordheim 2023). Metformin (1,000 mg twice daily) in combination with nivolumab (480 mg every 4 weeks) in a phase II trial in metastatic microsatellite stable CRC demonstrated immunomodulatory effects but not significant efficacy. Although metformin alone did not affect T-cell infiltration into tumors, the combination treatment increased tumor-infiltrating leukocytes and immune checkpoint receptors (Tim3+) levels, suggesting an immunomodulatory effect despite the lack of therapeutic benefit (Akce et al. 2023).
Preoperative metformin treatment in head and neck squamous cell carcinoma altered the tumor immune microenvironment (TIME) by decreasing the number of FOXP3+ T regulatory cells and increasing CD8+ T-cells in the tumor stroma, potentially enhancing the efficacy of immunotherapy (Amin et al. 2020). Similarly, in esophageal squamous cell carcinoma (ESCC), low-dose metformin altered the TIME by increasing the number of CD8+ T-cells and CD20+ B-cells while decreasing the number of tumor-promoting macrophages. This implies that metformin could be included in routine ESCC therapy to modulate the immune response (Wang et al. 2020). Combinatory treatment of rosiglitazone or metformin was performed with anti-PD-1 mAb in advanced solid malignancies such as NSCLC and melanoma (NCT04114136). Patients were randomly assigned to receive rosiglitazone, metformin, or anti-PD-1 alone. In this ongoing study, biopsies will be taken at baseline and after 5 weeks to evaluate the effectiveness of the treatment. The study will continue for up to 2 years or until toxicity or progression occurs. In NSCLC, trial combining the IACS-010759 inhibitor with radiation improved anti-tumor effects in a PD-1-resistant but less in PD-1-sensitive animal. It was observed that the addition of anti-PD-1 further improved the outcomes, suggesting that the combination of X-Ray (radiotherapy), IACS-010759 and anti-PD-1 may be an effective treatment for PD-1-resistant NSCLC (Chen et al. 2020). High OXPHOS levels in metastatic renal cell carcinoma (RCC) were associated with resistance to ICIs. Targeting OXPHOS in vivo using Ndufb8-knockdown cells resulted in decreased tumor development and enhanced CD8+ T-cell infiltration, indicating that OXPHOS inhibition may overcome ICI resistance in RCC (Tian et al. 2024). In the NCT05824559 study, patients with refractory metastatic CRC were treated with bevacizumab and ME-344. With a progression-free survival rate of 30.6% at week 16, the treatment was well-tolerated, although with limited disease control, indicating the need for additional studies of earlier lines of therapy (Boland et al. 2024).
Other targeted therapies and OXPHOS inhibitors
Temsirolimus, an inhibitor of the mTOR pathway, was investigated together with metformin in patients with advanced or recurrent endometrial cancer in this phase 1 trial (NCT01529593). Although the combination exhibited a limited response, it was safe and did not raise any further safety issues (Ahmed et al. 2025). A phase II clinical trial (NCT03675893) is investigating the efficacy of combining letrozole, an endocrine therapy, with abemaciclib, a CDK4/6 inhibitor, and adding metformin or zotatifin to the combination in the treatment of recurrent estrogen receptor-positive endometrial cancer. Preliminary results showed an objective response rate of 30%, with a median progression-free survival of 9.1 months (Konstantinopoulos et al. 2023). In patients with BRAF-mutated melanoma, study NCT03026517 is investigating the safety of using phenformin in addition to conventional BRAF and MEK inhibitors. This trial combines phenformin with dabrafenib and trametinib in BRAF V600-mutated metastatic melanoma and showed evidence of improved efficacy, justifying further evaluation (Chapman et al. 2023).
Challenges and limitations in OXPHOS-targeted therapy: side effects
Although drugs targeting OXPHOS are widely used in both preclinical and clinical studies, they may have their limitations such as toxicity or drive to MDF (Xu et al. 2020). Obviously, inhibiting an important process such as OXPHOS can be dangerous due to the fact that healthy cells use the same mechanisms of oxygen uptake and ATP synthesis as some malignant tumors, and therefore the use of inhibitors can and will cause different side effects.
Toxicity is a major factor, with side effects such as neurotoxicity, optic neuropathy, lactic acidosis, and gastrointestinal side effects often outweighing the minor therapeutic benefits of the drugs (Izreig et al. 2020, Chen et al. 2022, Liu et al. 2023b , Zhang & Dang 2023). For example, IACS-010759 in combination with metformin caused serious side effects, which limited their therapeutic use and required careful dosage modification (Sakellakis 2023). These inhibitors harm non-cancer cells, such as immune cells and mitochondria-dependent systems, leading to systemic toxicity and decreased antitumor immunity (Zhang & Dang 2023). While in vitro studies revealed protective effects of metformin and dexrazoxane from doxorubicin-induced cardiotoxicity, in vivo tests have failed, demonstrating side effects such as vomiting and inadequate energy intake (NCT02472353) (Sun et al. 2024).
The ME-344 clinical trial showed that at higher doses of 15–20 mg/kg, the following adverse events were observed: nausea, dizziness, and peripheral neuropathy (Bendell et al. 2015). The OCOG-ALMERA trial (NCT02115464) demonstrated that the addition of metformin to chemoradiotherapy in unresected locally advanced NSCLC resulted in worse treatment outcomes, including lower progression-free survival (34.8 vs 63%) and OS (47.4 vs 85%), making it inappropriate for patients with locally advanced NSCLC (Tsakiridis et al. 2021). In addition, tumor metabolic heterogeneity makes it difficult to identify clinically responsive patients (Kalyanaraman et al. 2022, Metts et al. 2023). Validation and development of effective predictive methods for biomarkers such as PGC1α/β remains a common challenge (Ghilardi et al. 2022). Another medical trial involving IACS-010759 identified several issues in the study, including dose-limiting toxicities that prevented the maintenance of therapeutic plasma concentrations of neurotoxicity. These included peripheral neuropathy and increased blood lactate levels. The toxic effects resulted in the inability to achieve doses required for consistent antitumor efficacy (Yap et al. 2023).
Despite promising preclinical results, several OXPHOS inhibitors have shown low efficacy in trials due to challenges such as insufficient activity, poor biodistribution, and lack of understanding of tumor metabolic vulnerabilities (Molina et al. 2018, Ghilardi et al. 2022). Small sample sizes, early study termination, and inadequate controls all contribute to reduced statistical power and generalizability in this area of research (Alistar et al. 2017, Fenn et al. 2020, Han et al. 2022, Seliger et al. 2022, Huang et al. 2023, Verma et al. 2023, Shah et al. 2024). Mixed patient populations and confounding results of individual treatment effects confound conclusions (Quintela-Fandino et al. 2020). In addition, the use of cell lines, small numbers of paired patient samples, and lack of immune system interaction studies contribute to poor study results (Zhang et al. 2019a , Cazzoli et al. 2023). Given these limitations, there is a need to improve research, more accurately categorize patients, and, if possible, develop new biomarkers and formulations.
Conclusion
For about a century, the field of cancer metabolism was dominated by the Warburg hypothesis that glycolysis stimulates tumor growth (Martins Pinto et al. 2023). This view has been disproved by recent data suggesting that many resistant cancers or CSCs still use OXPHOS to survive chemotherapy and radiation (Zhao et al. 2022). This quality paves the way for potential clinical targets to prevent recurrence, cancer resistance or as chemoprevention. This review examines the major mechanisms of tumor resistance associated with OXPHOS, including alterations in MMP, hypoxia-induced metabolic reprogramming via HIF-1α signaling, and enhanced mitochondrial biogenesis via PGC1α regulation. Ultimately, these findings suggest that OXPHOS is not just an auxiliary metabolic pathway, but rather a major player in therapy-resistant tumors and metabolic niches enriched with CSCs.
In light of the role of OXPHOS in tumor persistence, numerous inhibitors targeting mitochondrial complexes and metabolic pathways have been developed; however, the efficacy of drugs such as IACS-010759, CPI-613, metformin, phenformin, IM156, rotenone, atovaquone, ME-344, etc. has been controversial. Although some of them have shown clinical efficacy in reducing tumor progression and especially in overcoming drug resistance, their marked toxicity and the flexibility of tumor metabolism and the patient-specific dependence of OXPHOS profile have so far hampered their practical application.
What are some practical tips for using such compounds while mitigating side effects? First, it is the development of combinatorial approaches. Recent studies have focused on combining OXPHOS inhibitors with conventional therapies including immunotherapy, radiation, chemotherapy, and targeted therapies to overcome these limitations. While CPI-613 has demonstrated synergism with FOLFIRINOX in pancreatic cancer, metformin has shown promise in colorectal, ovarian and breast cancer in combination with chemotherapeutic agents (Broekman et al. 2020, Barakat et al. 2022, Akce et al. 2023). In metastatic colorectal cancer, ME-344 in combination with bevacizumab has shown some clinical potential (Boland et al. 2024). In addition, new studies show that effects on mitochondrial metabolism can increase the effectiveness of immune checkpoint blockade, which strengthens the arguments in favor of OXPHOS inhibition in cancer treatment (Boreel et al. 2021). Finding simple and inexpensive in vivo models can facilitate such studies. We recently developed a rapid model to study the effects of antimicrobials, potential OXPHOS inhibitors, on a population of the microcrustacean Artemia salina to show how some known drugs exert toxic effects on mitochondria, inhibiting cellular and organismal respiration in aquatic organisms (Fadda et al. 2025). This can be used for preliminary screening of potential new or repurposed drugs. Further studies should identify new combinations that can improve efficacy, allow personalized treatment based on metabolic profiling, and enhance the action of OXPHOS inhibitors to minimize off-target effects.
Second, one has to take into account the patient’s personalized metabolic profile. Despite hopeful advancements, challenges still exist, such as tumor heterogeneity, which impacts the effectiveness of treatment and toxicity (neurotoxicity, lactic acidosis, and metabolic disturbances). To determine which patients will benefit most, reliable biomarkers are needed, and further studies to maximize the optimization of combination therapies and understand how they interact with the immune system. For example, simple immunochemical analysis of OXPHOS proteins or OXPHOS gene expression levels taken from patient biopsy samples and compared to neighboring tissue samples, especially before and after treatment, may help avoid or reduce the cytotoxic burden of chemotherapy/radiotherapy. Metabolic imaging may also improve patient selection, thereby ensuring that therapy is tailored to maximize effect. Third, the reduction of cytotoxic action of OXPHOS inhibitors should be optimized by developing new delivery methods. In particular, TPP-bound compounds are able to accumulate directly in mitochondria, which makes it possible to reduce the total dose of drugs (Amatangelo et al. 2024) (10.3390/antibiotics10050489). It is also applicable to a combinatorial studies of OXPHOS inhibitors and immunotherapy. The comprehension of the effect of OXPHOS inhibitors on the tumor immune microenvironment becomes a substantial challenge because these medications can hinder the systemic immune system from producing pro-tumor cells, failing to initiate anti-tumor fighting.
In conclusion, while OXPHOS clearly plays a role in the resistance to cancer, translating the findings into therapies remains challenging. To properly exploit the inhibition of OXPHOS and hopefully allow for better treatment avenues against resistant and recurrent cancers, more studies and carefully designed clinical trials need to be conducted. Overcoming current challenges might bring in a new era in cancer treatment, providing stained hope to patients suffering from frustratingly resistant cancers.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/REM-25-0003.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.
Funding
AL and laboratory members were supported by the TUBITAK2232A program, an international fellowship for outstanding researchers (project 121C096) and TUBITAK1001 (project 124Z377).
Acknowledgments
The graphical illustrations used in this study were made using BioRender (biorender.com).
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