Intermittent fasting enhances cancer therapy via autophagy-dependent and independent mechanisms: Evidence and implications

Abstract

Macroautophagy (hereafter referred to as autophagy) is a lysosomal degradation pathway that clears and recycles cytosolic oncogenic factors, excess lipids, and damaged mitochondria, thereby potentially preventing cancer initiation. Recent studies using in vitro and animal cancer models, as well as clinical investigations in cancer patients, indicate that intermittent fasting exerts beneficial effects, particularly by reducing chemotherapy-related toxicity and slowing tumor growth through multiple mechanisms, including metabolic reprogramming, immune modulation, attenuation of inflammation, and upregulation of autophagy, among others. In this review, we briefly discuss the molecular mechanisms underlying intermittent fasting-mediated cancer prevention and therapy, including the role of autophagy and related clinical implications, highlighting its potential as a valuable adjunct to chemotherapy that warrants further large-scale investigations.

Key Words: Intermittent fasting; Cancer; Chemotherapy; Autophagy; Metabolic diseases; Obesity; Inflammation

Core Tip: Growing evidence indicates that intermittent fasting (IF) can reduce chemotherapy-related toxicity and slow tumor growth in cancer patients through both autophagy-dependent and independent mechanisms. Therefore, IF may represent a promising strategy for cancer prevention and as an adjuvant to cancer therapy. However, there are limitations associated with IF in cancer therapy.

INTRODUCTION

Cancer is a major global health problem and one of the leading causes of mortality, largely due to the lack of definitive therapies. Its development is driven by multiple mechanisms, including prolonged exposure to carcinogens, impaired DNA repair, immune suppression, dysfunction of macroautophagy (autophagy), chronic inflammation, excessive production of reactive oxygen species (ROS), elevated circulating insulin levels, and other factors[1]. Conventional cancer therapies such as chemotherapy, immunotherapy, and radiotherapy are expensive and associated with significant side effects, highlighting the urgent need for more effective and affordable treatments.

Caloric restriction (CR), a reduction in calorie intake without malnutrition, has demonstrated potential for preventing and treating cancer. Intermittent fasting (IF), a dietary regimen involving cycles of fasting and eating, has emerged as a more sustainable alternative to chronic CR, mimicking its benefits while potentially improving long-term adherence[2,3]. A growing body of evidence indicates that IF may serve as a strategy for cancer prevention and as an adjunct to chemotherapy, protecting healthy cells, enhancing cancer cell death, and reducing chemotherapy-associated side effects. These beneficial effects of IF are mediated primarily through autophagy as well as autophagy-independent mechanisms[1-3].

In this brief review, we summarize the various types of IF and discuss the mechanisms underlying its cancer-preventive and therapeutic effects, which may be autophagy-dependent or independent, based on evidence from preclinical and clinical studies.

METHODOLOGY AND REVIEW CRITERIA

This narrative minireview provides a concise synthesis of recent preclinical and clinical studies on the anticancer effects of IF, its underlying molecular mechanisms, and their clinical implications. It is based on a curated selection of relevant literature published over the past 10 years, highlighting current trends and key findings in the field. The databases consulted include PubMed, Google Scholar, the Directory of Open Access Journals, ScienceDirect, and others. The literature search was conducted using the aforementioned keywords. The various types of IF are summarized in Table 1[4-10].

Table 1 Different types of intermittent fasting regimen.

Subtype of intermittent fasting regimen	Description	Ref.
Alternate day fasting	Complete fasting or very low calories intake for 24 hours, every other day, every 3-4 days or 2 non-consecutive days per week; alternating with ad libitum feeding without restriction on the next day	[4]
Modified alternate day fasting	Fasting days with severe and specific calorie restriction, approximately 75% calorie-restricted on alternate days, with a single feeding on fasting days that allocates 25% of calorie requirements	[5]
5:2 diet	Two fasting days, either consecutive or non-consecutive (75% energy restriction), and five non-fasting days (No energy restriction) per week	[5,6]
Time-restricted feeding	An individual is allowed to eat within a feeding period of 4-12 hours and will fast for the rest of the day. Commonly practiced methods are: (1) 16/8 with a feeding period of 8 hours/day and 16 hours of fasting; and (2) 12/12 with equal feeding and fasting periods	[7]
Prolonged water-only fasting	Fasting for an extended period, usually carried out for 3 days to 21 days. During consecutive fasting days, only water is permitted without any food intake	[8,9]
Fasting-mimicking diet	Plant-based caloric-restricted diet (30%-50% of the normal caloric intake) for 4-7 consecutive days, followed by a refeeding ad libitum period once per month	[9]
Ramadan intermittent fasting	Obligatory fasting for Muslims in the month of Ramadan (29-30 days), which consists of no food or drink from dawn to sunset (approximately 12 hours)	[10]

MECHANISMS OF IF-INDUCED CANCER PREVENTION AND THERAPY

While autophagy has gained attention as one of the most fundamental mechanisms driving the anticancer activity of IF, recent studies establish several autophagy-independent processes involved in its prevention and therapeutic action. These processes involve diverse biological mechanisms such as metabolic regulation, adaptation to oxidative stress, immune response, hormonal signaling, and gut microbiota products. This section provides an overview of these mechanisms, supported by experimental and human studies.

Insulin/insulin-like growth factor 1 signaling suppression and metabolic reprogramming

One of the most well-characterized autophagy-independent mechanisms through which IF exerts anticancer effects is the suppression of insulin and insulin-like growth factor 1 (IGF-1) signaling, a pathway closely associated with tumorigenesis. Insulin and IGF-1 are potent anabolic hormones that promote cellular proliferation and survival, primarily through activation of the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin (mTOR) signaling axis, a pathway frequently dysregulated in malignancies[11]. Persistent elevations in insulin and IGF-1 levels have been epidemiologically linked to increased incidence and poor prognosis in various cancers, including breast, prostate, colorectal, and lung carcinomas[12]. IF consistently downregulates this axis by reducing nutrient intake and improving insulin sensitivity, leading to decreased circulating insulin levels and consequent hepatic suppression of IGF-1 synthesis[13,14].

Notably, this inhibition of IGF-1 signaling also induces a reversal of the Warburg effect, a hallmark of cancer metabolism wherein tumor cells preferentially utilize glycolysis even in normoxic conditions. By attenuating insulin/IGF-driven glycolytic flux, IF promotes a metabolic shift toward oxidative phosphorylation and ketogenesis, depriving cancer cells of their preferred energy substrate and reducing their proliferative efficiency[15]. Preclinical studies in colorectal cancer models demonstrate that IF increases oxygen consumption while decreasing adenosine triphosphate production in tumor tissues, culminating in enhanced apoptosis[16].

These findings are not confined to animal models. Human studies, particularly those examining Ramadan IF (RIF), have documented significant reductions in circulating IGF-1 levels within 3-4 weeks, especially among overweight or metabolically impaired individuals[13,14]. This metabolic reprogramming appears to selectively stress malignant cells, which are less metabolically flexible than normal cells. Moreover, fasting-induced hormonal modulation promotes cell cycle arrest and apoptosis in cancerous or pre-neoplastic cells, while simultaneously enhancing stress resistance and quiescence in healthy tissues, a phenomenon termed “differential stress resistance (DSR)”[11,17].

Importantly, IF may counteract chemotherapy-induced hyperinsulinemia, a side effect that can paradoxically promote tumor progression. Clinical data from breast cancer patients undergoing chemotherapy revealed that those adhering to an 18-hour fasting window around treatment cycles avoided the insulin and glucose spikes observed in non-fasting counterparts. This glycemic stability was associated with reduced toxicity and potentially enhanced therapeutic efficacy[17]. Collectively, these findings underscore that suppression of insulin/IGF-1 signaling constitutes a robust, clinically relevant anticancer mechanism of IF, operating independently of autophagic pathways and offering a metabolically targeted adjunct to conventional cancer therapies.

Reducing oxidative stress and DNA lesions

Oxidative stress and genomic instability are key contributors to carcinogenesis. IF counteracts these processes by suppressing ROS production and enhancing DNA repair capacity. Fasting-induced metabolic shifts, particularly toward fatty acid oxidation, reduce mitochondrial ROS generation, partly through activation of the nuclear factor erythroid 2-related factor 2 pathway, which upregulates antioxidant enzymes such as heme oxygenase-1, nicotinamide adenine dinucleotide reduced, nicotinamide adenine dinucleotide phosphate reduced quinone dehydrogenase 1[18]. Simultaneously, IF promotes genomic integrity by enhancing base excision repair and homologous recombination pathways, with sirtuin 1 activation facilitating DNA repair gene expression and chromatin remodeling. Human studies show that IF reduces oxidative stress biomarkers such as malondialdehyde and 8-hydroxy-2’-deoxyguanosine, while increasing antioxidant activity, supporting its cytoprotective role[19]. These adaptations collectively preserve genome stability, particularly in metabolically or inflammation-prone conditions.

Immune modulation and anti-inflammatory effects

IF reprograms immune dynamics in ways that enhance antitumor surveillance and reduce pro-oncogenic inflammation. Fasting transiently reduces circulating leukocytes, followed by hematopoietic stem cell-driven regeneration during refeeding, yielding a rejuvenated immune profile with enhanced cytotoxic T lymphocyte and natural killer cell activity. In a recent murine model, IF reprogrammed natural killer cell metabolism to improve survival and cytotoxicity within the tumor microenvironment, highlighting its role in direct antitumor effects[20]. This immune remodeling supports the clearance of abnormal or transformed cells and strengthens adaptive immune responsiveness.

Concurrently, IF downregulates key inflammatory mediators such as interleukin-6, tumor necrosis factor-alpha, and interleukin-1 beta, which are central to tumor-promoting microenvironments. These anti-inflammatory effects are observed consistently in human fasting protocols exceeding 48 hours, with reductions in circulating cytokines and C-reactive protein (CRP) levels[21]. Mechanistically, these effects are mediated by suppression of the nuclear factor-kappa B signaling pathway and activation of AMP-activated protein kinase (AMPK). A recent clinical trial in breast cancer patients combining fasting-mimicking diet with a ketogenic diet demonstrated enhanced AMPK activation and reduced tumor biomarkers[22].

Further supporting this, IF enhances CD8+ T-cell responses and immune memory in tumor-bearing mice, providing evidence of improved antitumor immunity[23]. These shifts create an immune environment that resists tumor development, supporting IF as a promising adjunctive strategy in cancer prevention and immune enhancement.

Endocrine and neuroendocrine modulation

IF exerts anticancer effects through complex hormonal rebalancing that extends beyond the insulin/IGF-1 axis. IF consistently reduces leptin, a pro-inflammatory and pro-tumorigenic adipokine, contributing to lower angiogenesis and improved tumor control. Although earlier hypotheses suggested increases in adiponectin, recent meta-analyses show that adiponectin levels typically remain unchanged with IF[24]. Nonetheless, IF mimics many of the metabolic benefits of CR, including downstream effects such as AMPK activation and mTOR inhibition, which do not necessarily require elevated adiponectin[25]. Clinical studies have reported improved leptin/adiponectin ratios and reductions in breast and colorectal cancer risk biomarkers in individuals undergoing IF interventions[26,27].

Moreover, IF impacts sex hormones relevant to hormone-sensitive cancers. Weight loss induced by IF reduces aromatization in adipose tissue, thereby lowering circulating estrogen levels in women, a key driver of estrogen receptor-positive breast and endometrial cancers. While direct evidence from IF trials in cancer patients remains limited, surrogate data from RIF and CR studies suggest reductions in cumulative estrogen exposure over time[28]. In men, IF has been associated with modest increases in testosterone and improvements in insulin sensitivity, with potential implications for prostate cancer risk[29].

Growth hormone (GH) secretion also increases during fasting, stimulating lipolysis and enhancing fatty acid availability. Importantly, while GH rises, hepatic GH resistance ensures IGF-1 remains suppressed, preventing sustained mitogenic signaling. This transient rise in GH may aid tissue repair and autophagy activation without the cancer-promoting effects associated with chronic GH/IGF-1 elevation[30].

IF also modulates the hypothalamic-pituitary-adrenal axis. Chronic stress elevates cortisol, impairing immune surveillance and promoting tumor growth. IF has been shown to normalize basal cortisol levels and restore diurnal rhythm, reducing systemic inflammation and oxidative stress. Studies confirm that short-term increases in cortisol and epinephrine during fasting do not impair immunity; instead, they may support hematopoietic stem cell mobilization and immune regeneration via β-adrenergic receptor-mediated pathways[31,32].

Thyroid function is also subtly affected, with reductions in triiodothyronine observed during fasting, a physiological adaptation that conserves energy. Lower triiodothyronine levels may reduce oxidative damage and cellular proliferation, contributing indirectly to tumor suppression. In parallel, enhanced melatonin levels during Ramadan fasting have been observed, which may support anticancer effects via antioxidant, antiangiogenic, and antiproliferative mechanisms. Furthermore, increased ghrelin levels during fasting may have protective roles in the gastrointestinal tract and may modulate anti-inflammatory pathways, although their role in carcinogenesis remains under investigation[33].

Microbiota-derived metabolites and gut-immune-cancer axis

Emerging research underscores the influence of gut microbiota in mediating fasting-related cancer benefits. IF induces beneficial shifts in gut microbiota, increasing anti-inflammatory species such as Akkermansia muciniphila and Bifidobacterium. These microbes produce short-chain fatty acids such as butyrate and propionate and secondary bile acids, which inhibit tumor growth through mechanisms including histone deacetylase inhibition and regulatory T cell activation. These bile acid-microbiota interactions collectively reinforce gut-liver axis integrity and immune modulation[34]. Moreover, IF remodels the bile acid pool, enhancing the activation of farnesoid X receptor (FXR), a nuclear receptor pivotal for lipid metabolism, intestinal barrier function, and hepatic detoxification. FXR activation has been shown to exert antiproliferative effects in hepatocellular and colorectal cancer models, in part by modulating inflammatory gene expression and promoting tumor-suppressive transcriptional programs. Through this coordinated microbiota-bile acid-FXR signaling axis, IF contributes to systemic anticancer effects beyond calorie restriction alone[35-37].

Epigenetic remodeling and sirtuin activation

IF induces widespread epigenetic changes, including alterations in DNA methylation and histone modification patterns. These changes influence gene expression related to cell cycle control, apoptosis, and differentiation. Sirtuins, particularly sirtuin 1 and sirtuin 6, are activated by fasting and play roles in tumor suppression via epigenetic silencing of oncogenes[38,39]. These effects are particularly relevant in aging populations where epigenetic drift contributes to cancer risk[40]. IF may thus serve as a non-pharmacological tool to recalibrate the epigenome in a cancer-protective direction.

Synergistic enhancement of chemotherapy and radiotherapy

IF improves the therapeutic index of conventional treatments by sensitizing cancer cells and protecting normal cells. Tumor cells, under metabolic stress during fasting, show reduced DNA repair capacity and increased apoptosis in response to genotoxic therapies. Conversely, normal cells enter a protective quiescent-like state, limiting off-target toxicity. This DSR model forms the basis for ongoing clinical trials investigating fasting protocols in combination with chemotherapy in breast, ovarian, and colorectal cancers[11,17,18].

Circadian rhythm modulation

IF plays a critical role in synchronizing peripheral metabolic processes with the body’s endogenous circadian rhythms. By restricting food intake to specific windows aligned with the light-dark cycle, IF enhances the rhythmic expression of core clock genes such as brain and muscle ARNT-like 1, period circadian regulator 2, and circadian locomotor output cycles kaput, which are increasingly recognized as tumor suppressors[41]. Disruption of circadian regulation has been implicated in carcinogenesis through impaired cell cycle checkpoints, altered DNA repair, and dysregulated metabolism[42]. IF restores these rhythms, thereby improving systemic hormonal balance, reducing inflammation, and enhancing metabolic efficiency. RIF with its strict dawn-to-dusk schedule, offers a natural model of circadian-aligned feeding that reinforces entrainment of physiological rhythms. Both preclinical and clinical studies of time-restricted feeding (TRF) have demonstrated improvements in insulin sensitivity, reductions in inflammatory markers, and modulation of cancer risk pathways via circadian reprogramming[41,42].

Microvascular and endothelial function

IF appears to remodel, rather than suppress, tumor vascular architecture. While angiogenesis is a hallmark of cancer progression, IF may influence the quality and function of tumor vasculature through indirect mechanisms. Evidence from hepatocellular carcinoma models shows that IF enhances tumor vascularization and reduces extracellular matrix stiffness, thereby improving drug delivery and intratumoral perfusion. These effects resemble vascular normalization rather than outright anti-angiogenesis[43].

Additionally, IF improves endothelial function systemically by increasing nitric oxide bioavailability, enhancing flow-mediated dilation, and reducing inflammation and blood pressure, factors that contribute to vascular health and may indirectly influence tumor perfusion[44]. Moreover, IF modulates the tumor microenvironment by attenuating pro-angiogenic signaling from tumor-associated macrophages, partly through the downregulation of chemokine (C-C motif) ligand 8 via the mTOR-hypoxia-inducible factor 1-alpha axis, especially under hypoxic conditions[45]. Thus, IF shapes vascular behavior through immune-metabolic reprogramming, supporting more efficient drug penetration rather than generalized suppression of angiogenesis.

Collectively, IF exerts broad-spectrum anticancer effects by targeting metabolic, hormonal, immune, microbial, and epigenetic pathways. These effects may complement or even enhance autophagy-mediated benefits, providing a robust framework for integrated cancer prevention and adjunctive therapy. Figure 1 presents a visual summary of these diverse pathways and their targets.

Figure 1 Mechanisms of intermittent fasting in cancer prevention and therapy. This figure depicts the proposed multidimensional anti-cancer mechanisms of intermittent fasting (IF), integrating metabolic, immunological, endocrine, and epigenetic pathways. IF attenuates oxidative stress and DNA damage, suppresses insulin/insulin-like growth factor 1 signaling, enhances immune surveillance, and improves vascular function. Additional mechanisms include modulation of gut microbiota-derived metabolites, alignment of the circadian rhythm, favorable endocrine adaptations, and activation of key epigenetic regulators, such as sirtuins. These interconnected mechanisms collectively enhance responsiveness to cancer therapy, positioning IF as a promising adjunctive strategy in integrative oncology. ROS: Reactive oxygen species; Nrf2: Nuclear factor erythroid 2-related factor 2; IGF-1: Insulin-like growth factor 1; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; NK: Natural killer; IL: Interleukin; TNF: Tumor necrosis factor; CRP: C-reactive protein; SIRT: Sirtuin; CCL8: Chemokine (C-C motif) ligand 8; HIF: Hypoxia-inducible factor 1; BMAL1: Brain and muscle ARNT-like 1; CLOCK: Circadian locomotor output cycles kaput; PER2: Period circadian regulator 2; SCFA: Short-chain fatty acid; FXR: Farnesoid X receptor; GH: Growth hormone.

AUTOPHAGY: MOLECULAR MECHANISMS AND SIGNALING PATHWAYS

As illustrated in Figure 1, many of the anti-cancer effects induced by IF are largely independent of autophagy, although mechanistic links to autophagic pathways have been reported. For example, reduced insulin and IGF-1 signaling during fasting suppresses the phosphoinositide 3-kinase-protein kinase B-mTOR pathway, thereby activating autophagy[25,46].

Autophagy is tightly regulated by autophagy-related (ATG) proteins, which mediate the sequestration of oncogenic factors within autophagosomes and their subsequent clearance by the lysosomal system. Suppression of mTOR and activation of AMPK in response to various stressors such as IF initiate the autophagic process. Key ATG genes include ATG5, ATG7, and Beclin-1, which are essential for the formation of the isolation (phagophore) or autophagosome membrane, ATG4 and microtubule-associated protein 1 light chain 3 (LC3)-II, which are involved in autophagosome maturation, and lysosome-associated membrane protein-2 and Rab7, which are crucial for autolysosome formation[46,47]. Autophagy can also occur in a selective manner, such as mitophagy (mitochondria), lipophagy (lipids), and endoplasmic reticulum autophagy[48].

Importantly, autophagy is monitored by measuring autophagic flux, the rate of autophagic degradation. In humans, this is estimated by measuring LC3-II levels in peripheral mononuclear blood cells treated with the lysosomal inhibitor chloroquine. Increased LC3-II and decreased p62 (LC3) indicate enhanced autophagic flux[46,47].

Mitophagy, primarily mediated by the PTEN-induced kinase 1-Parkin RBR E3 ubiquitin (PRKN)-protein ligase-dependent pathway, plays a crucial role in cancer prevention by eliminating damaged mitochondria, which are major sources of ROS with carcinogenic potential. Briefly, mitochondrial DNA damage, oxidative stress, and other stressors cause the stabilization of PTEN-induced kinase 1 - a sensor of mitochondrial dysfunction - on the outer mitochondrial membrane. This stabilization facilitates the recruitment of cytoplasmic PRKN to the damaged mitochondria, leading to their sequestration by LC3-mediated autophagosomes and subsequent degradation by lysosomes[48-52]. In lipophagic, lipid droplets (LDs) are selectively degraded via the autophagy-lysosome pathway. LC3 interacts with patatin-like phospholipase domain containing 2/adipose triglyceride lipase and lipase E/hormone-sensitive lipase on the LD surface, and under nutrient deprivation, LC3 recruits patatin-like phospholipase domain containing 2/adipose triglyceride lipase through its LIR motif to enhance LD hydrolysis[48].

AUTOPHAGY AS AN ANTICANCER MECHANISM

Autophagy contributes to oncosuppression via several mechanisms. Directly, it facilitates the clearance of oncogenic proteins and supports DNA repair processes. Consistent with this, Beclin-1-deficient mice exhibit a heightened susceptibility to hepatocellular carcinoma, lung carcinoma, and lymphomas. Similarly, genetic deletion of ATG5 or ATG7 in mice results in the formation of benign liver tumors[49].

Autophagy also exerts indirect tumor-suppressive effects, including the attenuation of inflammation: A recognized initiator of tumorigenesis[50-52]. In addition, impaired autophagy has been implicated as a key factor in the pathogenesis of metabolic dysfunction-associated fatty liver disease, which could progress to hepatic cancer[47,48].

Based on in vitro and animal studies, several forms of upregulated autophagy-mediated cancer cell death have been documented in response to chemotherapy, including apoptosis[11,53], autophagic cell death[54], and immunogenic cell death[55,56]. Accordingly, modulation of autophagy through IF may represent a promising therapeutic strategy in cancer prevention and treatment, which could be related to the DSR (Figure 2)[17,57]. In addition, IF can be combined with various treatments (such as chemotherapy, immunotherapy, or radiotherapy), potentially enhancing their efficacy and reducing cancer cell resistance[11]. However, in certain established cancers, chemotherapy can induce autophagy, which may contribute to the development of early therapeutic resistance[46].

Figure 2 Proposed model for intermittent fasting -induced autophagy upregulation in cancer prevention and therapy. In experimental cancer models, intermittent fasting-induced autophagy acts as a cellular stressor that enhances differential stress resistance during chemotherapy, protecting normal cells while promoting selective cancer cell death and increasing the efficacy of specific chemotherapeutic agents. Several forms of intermittent fasting-associated, autophagy-mediated cancer cell death have been documented[53-56]. DSR: Differential stress resistance.

IF-INDUCED AUTOPHAGY IN CANCER THERAPY: INSIGHTS FROM ANIMAL MODELS

Using cell lines, xenograft mice, and chemically induced mouse models, a recent study found that compared to normal feeding, IF (6-hour TRF) inhibited the initiation and progression of lung cancer by downregulating T cell immunoglobulin and mucin domain-containing protein and upregulating autophagy (evidenced by increased expression of the autophagy marker LC3-II, reduction of p62 and improved autophagic flux), resulting in tumor suppression[58]. Another preclinical study using a mouse xenograft model of human colorectal HCT116 tumor cells demonstrated that inhibiting ATG4B cysteine protease activity with S130, in combination with CR, led to the accumulation of LC3-II and p62 in cancer cells. This accumulation resulted in apoptotic cell death through caspase-3 activity[59].

In addition, alternate day fasting for 2 weeks reduced tumor growth in a mouse model of colon cancer. This was associated with increased expression of Atg5 and LC3-II/LC3-I, which are markers of autophagy, suggesting one potential mechanism for the effect of alternate day fasting independent of weight loss in mice[60]. Moreover, IF was found to mitigate age-related prostatic hyperplasia in animal models of prostate cancer through activation of autophagic pathways via Beclin-1/p62 modulation and reduction of oxidative stress[61].

IF-INDUCED AUTOPHAGY IN CANCER PATIENTS

In contrast to the extensive preclinical evidence, studies investigating the autophagic response to IF in humans with cancer remain limited. Notably, RIF (dawn-to-dusk fasting) has been reported to upregulate ATG genes, including ATG5, ATG4B, LC3-II, and lysosome-associated membrane protein-2 in individuals with obesity and metabolic dysfunction-associated fatty liver disease[47,62]. This upregulation was accompanied by reductions in body fat and circulating inflammatory cytokines. Such findings suggest that enhanced autophagy by IF may contribute to cancer prevention, given the well-established associations between obesity, chronic inflammation, and the incidence of several malignancies, including breast, liver, and pancreatic cancers[47,48,60,62].

In hepatocellular carcinoma, the pharmacologic induction of autophagy has been investigated. A phase I/II trial of sirolimus, an mTOR inhibitor that induces autophagy, demonstrated antitumor effects in patients with advanced hepatocellular carcinoma, highlighting the translational potential of autophagy modulation in oncology[63].

A retrospective study of 115 patients with stage IIIB colon cancer found Beclin-1 expression in 85.2% of tumors, localized to the cytoplasm, membrane, and nucleus. High expression was associated with a higher 5-year survival rate (67.3% vs 47.1%; P = 0.034), indicating that Beclin-1 may serve as a favorable prognostic biomarker and reflect a tumor-suppressive role of autophagy[64].

Another study by Zhuo et al[65] identified a three-gene mitophagy-related prognostic signature (PRKN, SRC, and voltage-dependent anion-selective channel protein 1) for pancreatic cancer using transcriptomic and clinical data. This model effectively stratified patients into high- and low-risk groups, with the high-risk group showing poorer overall survival, higher KRAS mutation frequency, and an immunosuppressive tumor microenvironment characterized by reduced CD8+ T-cell infiltration and increased macrophages. These findings highlight mitophagy-related genes as promising biomarkers for prognosis and personalized therapy in pancreatic cancer[65].

TUMOR TYPES, HETEROGENEITY AND SENSITIVITY TO IF

Tumor types and heterogeneity are important factors in cancer therapy. As mentioned above, most preclinical and clinical studies have investigated the beneficial effects of IF on breast[17,22,26,27,66] and colorectal cancers[16,35-37,59,60] via several mechanisms. This may be explained by the fact that these tumors are among the most sensitive to IF, as their growth and survival strongly depend on insulin/IGF-1 signaling, glycolytic metabolism, and inflammatory pathways - all of which are suppressed by fasting. Other tumor types, such as prostate cancer[29,61], hepatic cancer[43], pancreatic cancer[65], and lung cancer[58], have also been reported to be sensitive to IF. However, detailed discussions regarding the various IF-sensitive and -insensitive tumors are beyond the scope of this minireview and could be addressed in future comprehensive reviews.

CLINICAL TRIALS AND RECOMMENDED PROTOCOLS FOR IF IN CANCER THERAPY

As shown in Table 1 and described in the text above, various IF protocols have been applied in cancer therapy. The most common and best-studied IF protocols are short-term fasting (STF; 48-72 hours around chemotherapy)[17,66], fasting-mimicking diet[22], and TRF[66]. A few clinical studies have demonstrated that STF during chemotherapy improves treatment tolerance and reduces adverse effects. Typically, fasting began 36 hours before and ended 24 hours after chemotherapy, resulting in a total fasting duration of 60 hours. In a crossover trial involving 34 patients with gynecological cancers, STF around chemotherapy was associated with smaller declines in quality of life (Functional Assessment of Chronic Illness Therapy scores) and less fatigue compared with a normocaloric diet. STF was well tolerated, with no serious adverse events reported, supporting the need for larger clinical trials[17,67]. These protective effects of STF may be attributed to the DSR mechanism and the activation of autophagy[57]. However, detailed descriptions of clinical trial protocols, recommended fasting regimens, and contraindicated populations are beyond the scope of this review and should be addressed in future studies.

MONITORING THE THERAPEUTIC POTENTIAL OF IF IN CANCER

IF is a promising adjunct to cancer therapy through multiple mechanisms, as discussed above. It shows potential to limit tumor growth and reduce treatment-related toxicity, as supported by preclinical and recent clinical studies. Therefore, monitoring inflammatory markers (e.g., tumor necrosis factor-alpha), metabolic profiles (e.g., IGF-1), ATG genes (e.g., LC3, p62), gut microbiome composition, immunological parameters (e.g., CD8+ cells), and tumor imaging using positron emission tomography/computed tomography in both cancer models and humans could aid in evaluating treatment responses before and after IF[68,69]. In addition, tumor markers such as carcinoembryonic antigen could be monitored during IF, as reported in a recent study[10].

LIMITATIONS AND RISKS

There are several limitations and risks associated with IF in cancer therapy. Fasting is not universally safe; patients with malnutrition, active cachexia, or those at high risk of treatment-related weight loss are not advised to fast. Clinical judgment is essential in such cases[70,71]. Moreover, there is a potential dual-risk concern, as autophagy may protect certain established tumors. Therefore, tumor type-specific and stage-specific effects must be carefully considered[72]. Furthermore, uncertainty remains regarding optimal protocols, including fasting duration, fasting-mimicking diet composition, timing relative to chemotherapy or radiotherapy, and long-term safety, which should be standardized through larger randomized controlled trials with adequate follow-up[71,73].

CHALLENGES AND PERSPECTIVE

The above-mentioned findings primarily stem from small pilot or early-phase trials with limited sample sizes. Larger randomized controlled studies are essential to confirm efficacy, establish optimal fasting protocols, and ensure long-term safety in diverse cancer patient populations. Whether IF-related autophagy upregulation enhances cancer cell death in humans needs to be explored and monitored using imaging studies and other laboratory techniques for autophagy markers and flux. Moreover, IF may induce selective types of autophagy, such as mitophagy or lipophagic, which can be explored in cancer animal models and clinical trials.

CONCLUSION

IF not only prevents oncogenesis but also enhances the efficacy of specific cancer therapies through multiple mechanisms, including metabolic reprogramming, immune modulation, attenuation of inflammation, reduction of DNA damage, regulation of circadian rhythms, epigenetic remodeling, improvement of gut microbiota composition, and upregulation of autophagy. IF has the potential to limit tumor growth by inducing cancer cell death and reducing treatment-related toxicity via DSR, as supported by preclinical and recent clinical studies. However, larger randomized controlled trials are essential to confirm its efficacy, establish optimal fasting protocols, and ensure long-term safety across diverse cancer patient populations. Whether IF induces selective types of autophagy, such as mitophagy or lipophagic, in cancer patients remains to be explored. Furthermore, monitoring the therapeutic efficacy of IF using comprehensive laboratory and imaging approaches represents an important area for future investigation.