Cancer remains one of the leading causes of death worldwide (Wu et al., 2020). Recent global estimates report approximately 20 million new cancer cases and nearly 9.7 million deaths in 2022. These figures indicate a continuing upward trend, which is projected to worsen in the coming decades (Li et al., 2023). Predictive models suggest that global cancer incidence could exceed 35 million new cases annually by 2050 (Hu et al., 2021; Zhang et al., 2023), underscoring the urgent need for more effective therapeutic strategies. Notably, a growing body of evidence suggests that metabolic disorders, particularly diabetes mellitus, are associated with both increased cancer susceptibility and worse clinical outcomes. Epidemiological studies have consistently shown that individuals with diabetes are at greater risk of developing several malignancies, including liver, pancreatic, colorectal, and breast cancers (Tsilidis et al., 2015). Mechanistically, hyperinsulinemia, chronic inflammation, and altered metabolic signaling in diabetic patients may foster tumor initiation and progression.

Radiation therapy (RT) is one of the principal antineoplastic therapies, and it refers to various stages of cancer. The essence of RT is the application of ionizing radiation (IR) to address cancer. RT exerts its antineoplastic effects primarily through the induction of DNA damage, creating both single-strand breaks (SSBs) and double-strand breaks (DSBs) that can lead to cell death or block proliferation (Baidoo et al., 2013). In addition, ionizing radiation (IR) generates reactive oxygen species (ROS) such as hydroxyl radicals (•OH), superoxide anions, and hydrogen peroxide via water radiolysis, which can later impair nucleic acids, lipids, and proteins dose-dependently (Reisz et al., 2014). The direct and indirect effects of RT can promote tumor cell senescence, death, and even alterations in the tumor microenvironment (TME) by damaging the tumor cell genome, disrupting key intracellular metabolic processes, and inducing immune responses (Orth et al., 2014). Notably, radiotherapy resistance remains a major obstacle to effective cancer therapy. The mechanism of radiotherapy resistance is complex and poorly understood. Many of the mechanisms reported in the literature include DNA repair, cell cycle regulation, anti-apoptosis pathway, oxidative stress regulation, anoxic microenvironment, autophagy, mitochondrial function reprogramming, epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) properties, dynamic changes within the TME (Huang and Zhou, 2021; Chen et al., 2022).

TME plays a decisive role in shaping RT response through a multifaceted network of cellular and molecular interactions (Fig. 1). Far from being a static scaffold, the TME comprises cancer cells, immune regulators-including regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs)-stromal fibroblasts known as cancer-associated fibroblasts (CAFs), endothelial cells, and a dynamic extracellular matrix (ECM). These components interact and communicate through a network of cytokines, metabolites, and extracellular vesicles (Cao et al., 2025). One of the hallmark features of the TME is hypoxia, which stabilizes hypoxia-inducible factor-1α (HIF-1α), suppressing ROS formation and reducing the DNA-damaging efficacy of IR (Xia et al., 2024). In parallel, the immunosuppressive landscape of the TME—characterized by immune checkpoint upregulation and the presence of Tregs, TAMs, and MDSCs—undermines the immune activation typically triggered by RT (Li and Qiao, 2022). Another key contributor to RT resistance is the CSC subpopulation, which resists radiation via enhanced DNA repair, robust antioxidant responses, and metabolic reprogramming such as the Warburg effect and glutamine metabolism (An et al., 2023; Alden et al., 2022; Sriramulu et al., 2023). Furthermore, CAF-mediated ECM remodeling creates a dual barrier: physically hindering drug or radiation penetration, and biochemically sustaining tumor survival via secreted factors like TGF-β (Feng et al., 2022; Yang et al., 2020a). Recent strategies have explored TME-targeted radio sensitization, including combinations of RT with hypoxia modulators, immune checkpoint blockade, metabolic reprogramming agents, and ECM-targeting therapies (Cao et al., 2025; Xia et al., 2024). Despite these advances, the TME remains a highly heterogeneous and adaptive system, posing significant translational challenges. Addressing this complexity through precision targeting of TME components may hold the key to overcoming radiotherapy resistance.

Mitophagy, a term initially introduced by John Lemasters to define the selective autophagic degradation of mitochondria (Lemasters, 2005), is a depolarized-mitochondria encapsulation process within double-membraned autophagosomes for later degradation in lysosomes. Cellular mitophagy is the process by which cells selectively isolate and eliminate defective mitochondria through an autophagic mechanism. Mitophagy regulates cancer metabolic reprogramming, supports cellular homeostasis, cell stemness, and chemoradiotherapy resistance for better adaptation to TME, involving both the autophagy and ubiquitin-proteasome systems (UPS) (Lu et al., 2023). Through the targeted clearance of radiation-damaged mitochondria, mitophagy further promote resistance to radiotherapy in cancer cells. Overall, mitochondria serve as a central metabolic hub, orchestrating ATP production and supplying vital precursors for the biosynthesis of lipids, nucleic acids, and proteins (Boese and Kang, 2021). The regulation of mitochondrial metabolism and mitophagy is crucial for tumor cell adaptation to radiotherapy-induced stress, bolstering their survival capacity. Furthermore, increasing evidence has linked metabolic disorders such as diabetes mellitus to tumor progression and poor radiotherapeutic outcomes, partially through mechanisms involving mitochondrial dysfunction, chronic inflammation, and altered redox balance. These diabetes-related metabolic perturbations may further reshape the tumor immune microenvironment (TIME) and mitophagic activity, compounding therapy resistance (Tsakiridis et al., 2021).

This review will emphasize the central role of mitophagy in the radiotherapy immune microenvironment. It primarily elucidates the mechanisms by which radiotherapy-induced cellular injury initiates mitochondrial stress and subsequently activates autophagy. Furthermore, it systematically illustrates the alterations in mitochondrial dynamics resulting from such injury, along with the key regulatory signaling networks orchestrating mitophagy. In addition, the review will also explain the regulatory role of the immune microenvironment in modulating responses to RT, emphasizing how tumor-associated immune cells, in conjunction with mitophagy to facilitate tumor immune evasion. Additionally, the intricate crosstalk among mitophagy, radiotherapy resistance, and the immune microenvironment will be dissected to illuminate their interconnected regulatory networks, while also summarizing major mitophagy-regulating pathways under radiotherapy-induced stress and discussing the impact of type 2 diabetes mellitus (T2DM)-driven metabolic dysregulation on tumor radiosensitivity and the immune landscape. This review seeks to deliver a thorough understanding of their mutual relationships in cancer therapy, offering novel perspectives for optimizing therapeutic strategies.

Mitochondria are key regulators of cellular energy metabolism, redox balance, and cell fate. In the setting of radiation, mitochondria experience significant functional and structural changes as a result of increased ROS production and DNA damage. This section is organized into four subsections to provide a structured overview of these changes. First, we describe the fundamental characteristics and functions of mitochondria in maintaining cellular homeostasis. Second, we examine how radiotherapy induces mitochondrial stress through ROS accumulation and DNA damage, impairing mitochondrial membrane potential and electron transport. Third, we concentrate on radiotherapy -induced mitophagy, emphasizing its dual function in either promoting cell survival or enhancing cell demise, contingent upon the cellular context. Finally, we discuss the dynamic regulation of mitochondrial fusion and fission in response to radiation-induced injury, which coordinates with mitophagy to maintain mitochondrial quality control. Together, these interconnected processes determine the sensitivity or resistance of tumor cells to radiotherapy and offer potential targets for therapeutic modulation.

Mitochondria are organelles encased by membranes that serve as most of the chemical energy production necessary to sustain cellular bioenergetic and metabolic processes in eukaryotic cells (Boese and Kang, 2021). Mitochondria also engage in bidirectional communication in conjunction with the nucleus and other organelles to sustain intracellular homeostasis, facilitate cellular adaptive remodeling to stress, and aid in preserving the developmental pathway. They often refer to as the powerhouse of the cell, generating adenosine triphosphate (ATP) through oxidative phosphorylation coupled to the tricarboxylic acid (TCA) cycle coupled with electron transport-linked phosphorylation (OXPHOS) (Makinde et al., 2023), driving essential biochemical reactions needed for life. Under normoxic conditions, ATP is produced by a series of redox reactions, including those occurring during fatty acid β-oxidation (FAO) (Giachin et al., 2021). Mitochondria play multifaceted and essential roles in preserving cellular homeostasis, including apoptotic signaling, and regulation of both ROS and calcium (Coulson et al., 2024). Mitochondria are also the primary intracellular source of producing superoxide during oxidative phosphorylation, regulating iron metabolism and lipid metabolism, while dysfunctional mitochondrial accumulation can induce a variety of clinical disorders including heart failure, Parkinson's disorders, Alzheimer's disease, and malignancies (Liu et al., 2014a). Mitochondrial factors including ATP synthesis, mitochondrial membrane potential (ΔΨm), and ROS levels are closely related to radiation resistance (Tomita et al., 2021). Oxidative stress (OS) and DNA damage induced by radiotherapy can modulate these mitochondrial parameters, further enhance the resistance of cells to treatment.

Radiotherapy-induced mitochondrial dysfunction is mediated primarily by ROS-dependent DNA damage cascades (Averbeck and Rodriguez-Lafrasse, 2021a). High linear energy transfer (High-LET) particles lead to a substantial accumulation of ROS, which not only directly damages the mitochondrial membrane but also destroys mitochondrial DNA (mtDNA), causing a decline in membrane potential and dysfunction of the electron transport chain (Gao et al., 2008a). Radiation-associated induction of DNA double-strand breaks indirectly affect mitochondrial function through the ATM/ATR (ataxia–telangiectasia mutated and Rad3-related) signaling axis (Huang and Zhou, 2020), that activates the mitochondrial permeability transition pore (mPTP) (Robichaux et al., 2023), thereby exacerbating oxidative stress and mitochondrial damage. These damages collectively activate autophagy to clear dysfunctional mitochondria and maintain cellular homeostasis.

Mitophagy is selectively eliminate dysfunctional mitochondria after radiotherapy. Impaired mitophagy can result in dysfunctional mitochondria accumulation, which significantly promotes the initiation and developing of tumors (Dong and Zhang, 2024). Damaged mitochondria release ROS (Wu et al., 2020), which further promotes cell damage and apoptosis. Mitophagy can be initiated by many cellular stressors, including the depletion of mitochondrial membrane potential (MMP) (Yoo and Jung, 2018), oxidative stress, DNA damage, and gene mutations. It is initiated by the ubiquitination of damaged mitochondrial components, followed by recognition by autophagy-associated proteins such as Pink1/Parkin and SQSTM1 (p62) and pathways independent of ubiquitin driven via mitochondrial autophagy receptors, including as NIX, BNIP3, and FUNDC1 (Narendra et al., 2008a; Wei et al., 2023). Additionally, mitophagy can be modulated by non-canonical mechanisms involving ROS, such as through LC3 (microtubule-associated protein 1 light chain 3) and Beclin-1 (Picca et al., 2020). Mitophagy exerts a dual function in radiotherapy: on one hand, cancer cells respond to radiation-induced oxidative stress by removing aged and damaged mitochondria through mitophagy, which inhibits inflammation and further ROS propagation, exerting an anti-tumor effect. On the other hand, certain tumor cells repair radiation-induced damage via autophagy, further enhancing radio-resistance.

Mitochondria are active and flexible organelles that constantly processes critical for cellular survival and adaptation to varying conditions, such as those required for cellular expansion, mitosis and mitochondrial localization during differentiation (Murata et al., 2020). Cells regulate mitochondrial homeostasis primarily through fusion and fission in response to radiotherapy-induced mitochondrial damage. Low-dose radiation typically promotes fusion, while high-dose radiation tends to trigger fission (Gao et al., 2008b). Under mild stress, fusion helps repair and maintain mitochondrial function, whereas severe damage often triggers fission to isolate and remove dysfunctional mitochondria (Liu et al., 2025). Both fusion and fission influence mitochondrial morphology and function, directly impacting cellular responses after radiotherapy, such as damage repair and the autophagy initiation. In the context of radiotherapy-induced oxidative stress or mild injury, fusion alleviates ROS accumulation, restores mitochondrial membrane potential, and facilitates molecular exchange, thereby maintaining mitochondrial energy production and cellular homeostasis (van der Bliek et al., 2013).

Mitochondrial fusion in mammals is mediated by dynamin-like GTPases localized to distinct mitochondrial compartments: Mitofusins (Mfn1 and Mfn2) drive the fusion of outer mitochondrial membranes (OMM), while optic atrophy 1 (OPA1) governs the fusion of inner mitochondrial membranes (IMM). This compartment-specific machinery ensures coordinated remodeling of mitochondrial architecture in response to metabolic and stress signals (Grel et al., 2023). The processing of OPA1 is modulated by multiple regulatory factors, including presenilin-associated rhomboid-like (PARL) and paraplegin, which are involved in the splicing and processing of OPA1 to yield multiple isoforms (Cipolat et al., 2006; Ishihara et al., 2006). OPA1 cleavage, mediated by proteins such as Yme or OMA1, alters mitochondrial morphology, particularly under depolarizing conditions induced by mitochondrial uncouplers like CCCP, leading to further fragmentation of mitochondria (Head et al., 2009). SIRT3 catalyzes the deacetylation of OPA1, thereby augmenting its GTPase enzymatic activity and contributing to the regulation of mitochondrial fusion (Samant et al., 2014).

In response to severe mitochondrial damage caused by radiotherapy, fission becomes a key mechanism for mitochondrial regulation. Fission isolates damaged mitochondrial fragments from healthy ones, creating smaller pieces and facilitating mitophagy. This process is modulated by proteins such as dynamin-related protein 1(DRP1), which, upon activation, induces the contraction and fragmentation of the inner and outer mitochondrial membranes, separating the damaged segments (Losón et al., 2013). Alongside DRP1, other critical proteins like FIS1, MFF (mitochondria fission factor), and MID49/MID51(mitochondrial dynamics protein of 49 kDa and 51 kDa) play crucial roles in mitochondrial division, particularly in the recruitment of DRP1 to the mitochondrial surface. FIS1 and MFF assist in the localization of DRP1 to the division site, triggering membrane contraction, while MID49 and MID51 participate in the division of the OMM by interacting with DRP1. The coordinated action of these proteins enables efficient separation of damaged mitochondria, preparing them for later removal via mitophagy (Yu et al., 2020; König et al., 2021). Through fission, cells isolate and eliminate damaged mitochondria, reducing the spread of damage and preventing further harm from harmful molecules such as ROS and mtDNA. Radiation-induced ROS accumulation and disruption of mitochondrial transmembrane potential activate fission, leading to rapid mitochondrial division and the isolation of damaged regions, thereby promoting mitochondrial autophagy (Fig. 2). Some tumor cells may enhance their resistance to radiotherapy by accelerating mitochondrial fission, which isolates damaged mitochondria and facilitates mitophagy, thereby reducing the extent of radiation-induced damage (Averbeck and Rodriguez-Lafrasse, 2021b).

Radiotherapy is essential in driving intricate, dynamic alterations within the TME, affecting immune reactions and mechanisms of resistance. In the early phase of RT, tumor cells typically undergo cellular damage, DNA damage, and stress responses, which trigger autophagy to maintain cell survival (Li et al., 2023; Caves et al., 2018; Lam and Goldszmid, 2021). In the early active autophagy phase, mitophagy helps eliminate dysfunctional mitochondria, reducing oxidative stress, maintaining cellular homeostasis, and preventing cell death. Additionally, mitochondrial stress promotes the initiation of innate immune pathways by promoting the secretion of DAMPs and tumor antigens (Sliter et al., 2018). In later stages, tumor cells may downregulate PINK1-mediated mitophagy to reduce the release of mitochondrial DAMPs such as mtDNA and ATP, thereby impairing dendritic cells (DCs) maturation and CD8+ T cell activation (Xie et al., 2023). Furthermore, blocked mitophagy in tumor cells can drive the persistence of impaired mitochondria, stabilizing HIF-1α and subsequently upregulating PD-L1 expression, ultimately fostering immune evasion (Shida et al., 2016; Pandey et al., 2024).

Impaired mitochondria not only forfeit their capacity to generate ATP and other biosynthetic precursors but also exacerbate oxidative stress and trigger apoptosis (Xue et al., 2001). The specific mechanism of mitophagy which tags dysfunctional mitochondria for removal via autophagosomes. Increasing researches suggest that damaged mitochondria are probably eliminated through a unique pathway distinct from general autophagy. Lemasters et al. first introduced the concept of mitophagy in 2005, highlighting that mitochondrial damage acts as a signal to trigger this process (Elmore et al., 2001). In 2008, Parkinson protein 2 (Parkin) was reported to be recruited to depolarized mitochondria, thereby facilitating their autophagic degradation (Narendra et al., 2008b). This study is widely considered a milestone in the field of mitophagy. Since then, studies on mitophagy have continued to progress, giving rise to the discovery of numerous mitophagy-related pathways and mitophagy receptors including BNIP3L (Sandoval et al., 2008a), FUNDC1 (Liu et al., 2012), PHB2 (prohibitin2) (Wei et al., 2017) and MCL-1 (myeloid cell leukemia-1) (Cen et al., 2020) etc. Therefore, the regulation of mitophagy holds significant potential for improving cancer treatment and offers new pathways for the creation of targeted therapies and individualized treatment approaches.

PINK1 (PTEN-induced putative kinase1) was first outlined by Unoki and Nakamura in 2001 (Unoki and Nakamura, 2001). It is crucial for regulating mitochondrial quality (mitoQC), maintaining active mitochondrial networks, and managing the selective degradation of dysfunctional mitochondria through autophagy (McWilliams and Muqit, 2017). In physiological conditions, PINK1 is translocated into mitochondria and subsequently cleaved by the mitochondrial rhomboid proteinase PARL (Jin et al., 2010; Deas et al., 2011). The processed PINK1 fragment is subsequently liberated into the cytoplasm, where it undergoes constant deterioration mediated via the E3 ubiquitin ligases UBR1, UBR2, and UBR4 (Eldeeb and Ragheb, 2020). However, upon mitochondrial depolarization, PINK1 is no longer subjected to cleavage by PARL and instead localizes to the OMM, where it initiates mitophagy signaling (Okatsu et al., 2013). Notably, mitochondrial injury induced by radiotherapy has also been shown to trigger PINK1 buildup on the OMM as a dimer bound to the TOMM complex to decrease the mitochondrial uptake of freshly produced proteins, highlighting its role in the stress-induced mitophagy response (Lazarou et al., 2012; Okatsu et al., 2015).

PINK1 dimerization subsequently triggers trans-autophosphorylation, a prerequisite for the recruitment of the E3 ubiquitin ligase Parkin. Phosphorylation of Parkin at serine 65 (Ser65) promotes its initiation and recruitment to damaged mitochondria (Kane et al., 2014a; Kazlauskaite et al., 2014a). Upon activated, Parkin ubiquitinates multiple OMM proteins, thereby promoting the localized formation of phagophores through interactions with LC3 via LIR (LC3-interacting region) domains (Kane et al., 2014b). In addition, several proteins participate in the regulation of PINK1 stability, including TOMM7 (a subunit of the TOM complex) (Sekine et al., 2019; Hasson et al., 2013), IMMT (an inner mitochondrial membrane protein) (Akabane et al., 2016), and the mitochondrial protease OMA1 (Sekine et al., 2019; Sekine, 2020).

Parkin is autoinhibited in the cytosol under unstressed conditions. It is unable to bind E2 ubiquitin-conjugating enzymes or perform its ubiquitination function (Koyano et al., 2014). PINK1 triggers Parkin activation via phosphorylation the Ser65 residue of ubiquitin, resulting in the application of the OMM coating with phospho-ubiquitin (pSer65-ubiquitin). Parkin then binds to this pSer65-ubiquitin, resulting in its translocation to the OMM (Kazlauskaite et al., 2014b). Upon binding, Parkin undergoes a conformational shift that releases its N-terminal ubiquitin-like (UBL) domain and repressor element of Parkin (REP) domains from inhibitory sites. This allows Parkin to interact with the E2 enzyme and initiate ubiquitination of OMM proteins (Narendra and Youle, 2024). Upon activation, Parkin ubiquitinates OMM proteins, which then form a signal that recruits autophagy adaptors like optineurin (OPTN), CALCOCO2/NDP52 (calcium binding and coiled-coil domain 2), and TAX1BP1 (Wild et al., 2011; Thurston et al., 2009). These adaptors help assemble the autophagy machinery, initiating autophagosome biogenesis around the dysfunctional mitochondria. The autophagosomes then merge with lysosomes, leading to the damaged mitochondrial degradation and the removal of potentially harmful mitochondrial stress following radiation. In a word, under radiotherapy-induced stress, PINK1 accumulates on damaged mitochondria, activates Parkin through phosphorylation, and together they trigger a mitophagic response to clear the damaged organelles, thereby maintaining cellular homeostasis and protecting cells from further mitochondrial dysfunction (Fig. 3). In additions, the PINK1 and PRKN genes interact with several genes linked to mitochondrial dynamics, such as Drp1, MFN, and OPA1. Recent research has shown that PINK1 can phosphorylate Drp1S616 to regulate mitochondrial fission. Additionally, PINK1 and PRKN influence mitochondrial signaling (PRKA/PKA), calcium homeostasis, and mitochondrial chaperones (Shou and Huo, 2022).

PHB2, a key component of the IMM, has recently emerged as a crucial receptor for mitochondrial autophagy. This protein plays a vital function in maintaining mitochondrial integrity, participating in the selective clearance of malfunctioning mitochondria for sustaining cellular homeostasis. PHB2 and its binding partner prohibitin form a ring-shaped macromolecular complex localized to the IMM, termed the PHB complex, which serves as an evolutionarily preserved and context-dependent longevity modulator (White, 2016a; Lahiri and Klionsky, 2017; Lourenço and Artal-Sanz, 2021). The complex regulates mitochondrial protein processing and degradation through modulation of mitochondrial proteolytic enzymes such as the ATPases Associated with diverse cellular Activities(m-AAA) proteases. These proteases are crucial for preserving the homeostasis of proteins in the mitochondria. PARL mediates the processing of substrates such as PINK1 and PGAM5, whereas OMA1 and YME1 are primarily is charge of the processing and degradation of OPA1(Lu et al., 2014; MacVicar and Langer, 2016). Recent studies, including those by Chaojun Yan et al., have highlighted PHB2's involvement in the mitophagy pathway that is dependent on PINK1 and Parkin. PHB2 facilitates mitophagy by modulating the PARL–PGAM5–PINK1 signaling axis, underscoring its multifaceted role in mitochondrial maintenance and its interaction with the autophagy machinery, including LC3 binding (Yan et al., 2020). Furthermore, in conjunction with its function in mitochondrial quality control, PHB2 has garnered increasing attention for its role in influencing cancer treatment efficacy, particularly in contributing to resistance against radiochemotherapy. PHB2's regulatory role in this process may play a pivotal part in modulating the cellular response to radiation-induced damage. In the context of radiochemotherapy resistance, PHB2's capacity to mediate mitochondrial autophagy has been linked to the regulation of mitochondrial function (Zhang et al., 2024). PHB2 promotes autophagy by binding to LC3, promoting the removal of impaired mitochondria. However, the interaction between PHB2 and LC3 can be competitively inhibited by protein disulfide isomerase (PDI), which reduces the autophagic response and thus lowers radiation sensitivity (Li, 2021). Furthermore, the small molecule FL3, which targets the PHB2-PARL-PGAM5-PINK1 pathway, has shown promising results in inhibiting malignant cell proliferation, highlighting PHB2 as a potential therapeutic target for improving RT outcomes. Future research into PHB2's multifaceted role in mitochondrial autophagy may provide new insights into overcoming therapy resistance in cancer.

MCL-1, a crucial anti-apoptotic protein, serve as a regulator in regulating mitophagy by interacting with key signaling pathways (Modi and Sankararamakrishnan, 2017). It stabilizes mitochondrial function and helps maintain mitochondrial homeostasis by inhibiting pro-apoptotic proteins. MCL-1's involvement in mitophagy is closely linked to the PINK1/Parkin pathway, where it may influence mitochondrial clearance by altering the recruitment of LC3 and other autophagy receptors. The anti-apoptotic protein MCL-1 collaborates with LC3 to facilitate mitophagy, the selective elimination of impaired mitochondria. This mechanism is competitively suppressed by protein disulphide isomerase (PDI), which interferes with the MCL-1-LC3 connection, thereby diminishing cellular vulnerability to radiation-induced mitochondrial stress (Moyzis et al., 2022). The protein also stabilizes PINK1, modulating the PARL-PGAM5-PINK1 pathway to regulate mitochondrial autophagy, which may contribute to resistance to radiotherapy. Therefore, targeting MCL-1 and its regulatory pathways could offer novel therapeutic strategies in diseases such as cancer and neurodegenerative disorders (Fig. 4).

The OMM harbors several LIRs within autophagy receptors, including BNIP3 (Bcl-2 interacting protein 3), NIX(BNIP3L), and FUNDC1(FUN14 domain contains 1). These proteins directly bind LC3 to activate mitophagy in mammalian cells (Liu et al., 2014b). Recent research has demonstrated that mitophagy mediated by receptors is controlled through the reversible protein phosphorylation proteins, which is essential for mitophagy regulation. Among these receptors, BNIP3 plays a role in all stages of mitochondrial autophagy, while the NIX pathway is well-established for receptor-dependent mitophagy. Both BNIP3 and NIX, as OMM proteins with LIRs, interact with LC3 on autophagosomes to selectively engulf damaged or aged mitochondria (Mizushima and Komatsu, 2011). BNIP3's high expression can trigger mitochondrial autophagy, but excessive autophagy may lead to apoptosis, as reported by Xiaoqing Liu et al. (2022). Furthermore, BNIP3 phosphorylation facilitates its interaction with LC3b and GATE-16(the ATG8 family member), enhancing mitochondrial isolation, autophagic flux, and degradation.

In addition to BNIP3 and NIX, FUNDC1 is another key player in mitophagy (Sandoval et al., 2008b). In 2013, Liu et al. reported FUNDC1 as a novel hypoxia-induced mitophagy protein (Wu et al., 2014). FUNDC1, like BNIP3 and NIX, contains an LIR motif and directly interacts with LC3. Under physiological conditions, the activity of FUNDC1 is negatively regulated through phosphorylation mediated by Src kinase (Chen et al., 2016). However, under hypoxic conditions or when stimulated by mitochondrial uncouplers like FCCP, FUNDC1 becomes dephosphorylated and exhibits a stronger affinity for LC3, promoting the localization of autophagic bodies to damaged mitochondria (Ding and Yin, 2012). Moreover, radiotherapy exacerbates hypoxia within tumors by damaging intratumoral blood vessels, which limits oxygen supply and alters the tumor microenvironment. In this context, ULK1 and ULK2(serine/threonine kinases) are recruited to impaired mitochondria, where they bind to FUNDC1 and phosphorylate it at Ser17, enhancing its interaction with LC3 and triggering mitophagy (Fig. 5) (Wu et al., 2016).

After radiation-induced damage, regulatory factors such as p53, mTOR, and AMPK play pivotal roles in the modulation of mitophagy, helping cells manage stress, repair damage, metabolic homeostasis, apoptosis, and autophagy (White, 2016b; Cordani et al., 2016; Song et al., 2024). p53, widely recognized as the "guardian of the genome," plays a multifaceted function in cellular integrity. Apart from triggering apoptosis and cell cycle halt in reaction to DNA damage, p53 also facilitates mitophagy by modulating the PINK1/Parkin signalling pathway. Moreover, it influences the expression of mitophagy-associated genes such as DRP1, a key regulator of mitochondrial division (Yin et al., 2021a). Recent studies have revealed that IR induces a pulsatile p53 expression pattern (Cordani et al., 2016). Nutlin-3a, as a small-molecule that activates p53, has been shown to convert this transient, oscillatory expression into a sustained activation profile, thereby redirecting cellular fate from survival toward senescence (Purvis et al., 2012). However, autophagy suppression prevents cellular senescence (Young et al., 2009). Notably, p53 exhibits multifaceted roles in both autophagy and mitophagy. Specifically, p53 facilitates autophagy through the activation of AMPK and the inhibition of mTORC1. Moreover, nuclear p53 facilitates the suppression of mTORC1 signaling by upregulating several upstream inhibitors, such as AMPK β-subunits, TSC2, PTEN, and Sestrin-1 and Sestrin-2. Recent findings underscore its central role in modulating autophagic flux, particularly under genotoxic stress or periods of nutrient shortage (Budanov and Karin, 2008; Feng et al., 2007). On the other hand, studies have shown that the presence of a cytoplasmic form of p53 can prevent extensive mitophagy in various tissues and cell types (excluding skeletal muscle) under various stress and nonstress conditions (Tasdemir et al., 2008). mTORC1 negatively regulates mitophagy by inhibiting the transcription of autophagy-initiating genes, including ULK1 (Yin et al., 2021b). In contrast, mTORC2 may indirectly affect mitophagy through signaling molecules like AKT. Following radiation, the inhibition of mTOR triggers autophagy, aiding in the removal of damaged mitochondria. Similarly, AMPK, which senses energy stress, activates mitophagy by inhibiting mTORC1 and upregulating upstream signaling pathways like LKB1. This coordinated action of p53, mTOR, and AMPK ensures the efficient clearance of damaged mitochondria, restoring cellular energy balance and promoting survival under stress conditions.

Mitophagy mediates radiotherapy resistance through its anti-apoptotic effects, its role in metabolic reprogramming, and by regulating antioxidant defenses. These mechanisms work in concert to ensure the survival of cancer cells under radiation stress, making mitophagy a potential target for therapeutic interventions designed to overcoming radiotherapy resistance.

Radiotherapy induces significant mitochondrial stress, characterized by mitochondrial DNA damage and ROS production. Mitophagy stabilizes cellular energy metabolism and inhibits the production of pro-apoptotic molecules such cytochrome c and Bax (BCL-2-like protein 4). By maintaining mitochondrial integrity, including preventing mitochondrial outer membrane permeabilization (MOMP), mitophagy exerts an anti-apoptotic effect. MOMP can be triggered by the pore-forming activity of proapoptotic proteins such as BAX and BAK1, or by mitochondrial permeability transition (MPT) (Averbeck and Rodriguez-Lafrasse, 2021c; Su et al., 2023). Extrinsic apoptosis is initiated through apoptosis receptors, triggering caspase 8 activation, which subsequently initiates downstream executioner caspases. The intrinsic apoptotic pathway is connected to the extrinsic pathway by caspase 8-mediated cleavage of BID (BH3-interacting domain death agonist), facilitating its translocation to the mitochondria, which initiates MOMP, hence enhancing the apoptotic signal (Huang et al., 2016). In this context, mitophagy's anti-apoptotic effect defends cells against radiation-induced death, contributing to the persistence of neoplastic cells and ultimately fostering therapeutic resistance.

Metabolic reprogramming is recognized as a distinguishing feature of cancer, enhancing tumorigenic potential (Martínez-Reyes and Chandel, 2021). Recently, growing evidence has demonstrated that metabolic changes contribute to radioresistance in various cancers (Zhou et al., 2020; Rashmi et al., 2018). Radiotherapy-induced mitochondrial stress leads to shifts in the metabolism of cells, and mitophagy serves as an essential function in facilitating this reprogramming. By selectively degrading dysfunctional mitochondria, mitophagy helps maintain mitochondrial homeostasis, ensuring optimal energy production through oxidative phosphorylation (Lou et al., 2020). In turn, this supports the altered metabolic demands of cancer cells under radiation stress. Additionally, mitophagy promotes the survival of cancer cells by ensuring metabolic flexibility (Kubat et al., 2023), allowing them to switch between glycolysis and oxidative phosphorylation as needed. This metabolic reprogramming not only ensures cellular energy supply but also contributes to resistance by sustaining the bioenergetic status of tumor cells under treatment-induced stress.

In metabolically compromised conditions such as T2DM, cancer cells may exhibit further dysregulation of mitochondrial metabolism. Persistent hyperglycemia, insulin resistance, and elevated oxidative stress in T2DM disrupt mitochondrial function and impair mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased mitochondrial ROS generation (Palsamy and Subramanian, 2011; Hallakou-Bozec et al., 2021). These changes may paradoxically activate cytoprotective responses—including antioxidant defenses and DNA repair mechanisms—that help tumor cells tolerate radiotherapy-induced damage. Moreover, aberrant activation of nutrient-sensing pathways, such as PI3K-AKT-mTOR signaling, can synergize with cancer-specific metabolic rewiring to enhance survival under radiation stress (Chiefari et al., 2021; Parama et al., 2022).

Oxidative stress is considered as tumor cells continuously strive to maintain a balanced redox state. Antioxidant redox systems in various cellular compartments, including glutathione, NADPH, thioredoxin (Trx), and peroxidases like peroxiredoxins (Prx), do not maintain equilibrium but are individually controlled at different redox potentials (Jones, 2006; Valko et al., 2016; Lennicke and Cochemé, 2021). Oxidative stress can, therefore, be regarded as the chronic dysfunction of these redox systems and redox-sensitive signaling pathways. The mitochondrial antioxidant defense mechanism normally controls the amount of ROS within the organelles, enabling the secretion of low levels of mitochondrial H2O2 into the cytosol to function as cell survival signal transducers (Zhang et al., 2022; Sies and Jones, 2020). Mitochondria are the principal source of ROS production, due to their function in energy generation through the electron transport chain (Kausar et al., 2018). However, excessive production of ROS following radiotherapy results in additional mitochondrial damage, thereby perpetuating a detrimental cycle. To counteract this accumulation of ROS, mitochondria possess a variety of antioxidant defense systems, such as glutathione peroxidase, thioredoxin reductase, and mitochondrial superoxide dismutases (SOD) (Mailloux, 2018). These systems reduce oxidative stress, thus minimizing cellular damage and preventing apoptosis. Mitochondrial plasticity represents another significant challenge to mitochondrial integrity, which necessitates ongoing changes in the mitochondrial proteome to meet cellular demands (Ahola et al., 2019). However, when mitochondrial impairment surpasses the capability of cellular quality control mechanisms, damaged mitochondria are eliminated from the network via mitophagy (Lemasters, 2014). Yang Liu et al. showed that disruptions in mitochondrial homeostasis and redox balance are frequently associated with dysregulated mitochondrial dynamics, defective mitophagy, and alterations in the glutathione/glutathione disulfide redox system. the dysregulation of the redox system often causes radioresistance and decreases the radiotherapy effectiveness (Liu et al., 2018).

TME, composed of those that engage directly or indirectly with tumor cells via the secretion of chemokines and cytokines, constitutes a spatially organized framework. Within this structure, T lymphocytes and macrophages are primarily localized in both the central areas and the invasive margins (Bader et al., 2020). Certain lymphocytic populations, including Tregs and Th17 cells, promote tumor progression, whereas the majority of T cell subsets, including Th1, Tfh, and cytotoxic T cells, exert anti-tumor effects. CD8+ T cells are particularly abundant in tumors characterized by a high mutational burden, notably involving such as microsatellite instability (MSI) cancers, UV-related melanomas, or those adducts with mutagenic DNA such as lung cancers (Sautès-Fridman et al., 2020). Other elements of the cellular-mediated immunological response, encompassing innate immune cells such as MDSCs, NK cells, mast cells, and neutrophils, are primarily concentrated at the invasive edges. Other cellular populations, including B lymphocytes and matured DCs (mDCs), are more commonly located in the tumor-adjacent lymphoid structures (TLS). The distribution of these immune cells in the microenvironment is directed via the presence of vascular, lymphatic networks, and the supportive fibroblastic stroma (Sharma and Pruschy, 2017).

RT exerts a dual influence on the immune microenvironment (IME), producing either immunogenic or immunosuppressive effects. The effects are determined by multiple parameters, including host immunological status, tumor histology, radiation dosage and fractionation schedule, as well as the volume and anatomical location of irradiated normal tissue (Lynch et al., 2024). Suit and Kastelan et al. demonstrated that effective tumor control necessitated the administration of higher radiation doses in immunosuppressed mice compared to tumors in immunocompetent mice (Stone et al., 1979). Following radiotherapy, the TME enters a "plastic" phase, particularly during the acute phase. Within hours to a few days after the initiation of radiotherapy, radiation may induce direct tumor cell death. However, due to the relatively low reactivity of immune cells localized to tumors, suppressive cells (including Tregs and MDSCs) may dominate, leading to immune suppression (Veglia et al., 2021). Weeks to months after radiotherapy, as tumor cell death releases antigens, immune cells are recruited and activated, gradually stimulating the host immune response. Additionally, irradiation has been indicated to eradicate tumor-induced suppressor T lymphocytes in murine models, resulting in improved adaptive immunity (North, 1984). During this phase, signs of immune activation may emerge, including CD8+ T cell infiltration and DCs activation (Weichselbaum et al., 2017a). The combination of immunotherapy (like CAR-T cells and immune checkpoint blockade) with radiotherapy can modulate the immune functional status of the TME post-radiotherapy. Anti-PD-1 and anti-CTLA-4 inhibitors are examples of immune checkpoint inhibitors (ICIs) that can overcome radiotherapy-induced immune suppression, activate T cell-mediated anti-tumor responses, and promote the establishment of an immunoactivating microenvironment.

The heterogeneity of the IME, characterized by "hot" (immune-active) and "cold" (immune-suppressive) tumors, is a key determinant of radiotherapy sensitivity. Advances in combination therapies—such as RT combined with ICIs, cytokine therapies, and metabolic modulators—offer potential solutions to mitigate resistance and enhance treatment efficacy.

Radiotherapy is a crucial instrument in the domain of immunotherapy owing to its potential to elicit anti-tumor immune activity through immune modulation. Radiotherapy enhances tumor cell immunogenicity by altering their phenotype and reshaping the TME, thereby inducing and subsequent immune cell activation triggering immunogenic cell death (ICD). The ICD induces the release of TAAs and damage-associated molecular patterns (DAMPs). These DAMPs include surface-exposed calreticulin (CRT) and heat shock proteins (HSP70 and HSP90), ATP, and high-mobility group box1 (HMGB1). Additionally, ICD promotes the secretion of type I interferons (IFNs) and cytokines belonging to the interleukin-1 (IL-1) family. These molecules collectively enhance the antigen presentation capacity of antigen-presenting cells (APCs) like DCs, thereby activating T cells and triggering adaptive immune responses that target surviving tumor cells (Sharabi et al., 2015; Lee et al., 2009a; Deng et al., 2014; Frey et al., 2016). Lhuillier et al. reported identifying “neoantigens” from somatic nonsynonymous mutations, which are overexpressed following radiotherapy and are recognized by tumor-specific T cells (Lhuillier et al., 2021). Although, this mechanism is well-supported in vitro and animal models, the precise processes by which radiotherapy induces anti-tumor T cells remain poorly characterized, especially in terms of differential responses across various tumor types.

Radiotherapy also has significant effects on the TME. Satish Kumar R Noonepalle indicated that acute pro-inflammatory responses mediated by M1 macrophages and the damage to cellular DNA are observed following radiotherapy (Noonepalle et al., 2023). Furthermore, the cGAS-STING signaling pathway is activated by tumor cell DNA released into the cytoplasm. This activation promotes the secretion of interferon-β (IFN-β) by cancer cells (Chen et al., 2019). In turn, IFN-β enhances Batf3-dependent DC recruitment and activation. These DCs subsequently stimulate CD8+ T cells, contributing to systemic cancer rejection—also known as the abscopal effect—following radiotherapy (Vanpouille-Box et al., 2017). These processes suggest that radiotherapy not only increases T cell infiltration but also significantly enhances T cell-mediated cytotoxicity by promoting the production of TNF tumor necrosis factor-α (TNF-α), IFN-γ, and granzyme B (Hay and Slansky, 2022). In the majority of murine cancer models, especially CD8+ T cells, as their depletion significantly diminishes the anti-tumor effects of RT (Lee et al., 2009b; Weichselbaum et al., 2017b). However, existing evidence does not suggest a crucial function of CD4+ T cells in reaction to RT in majority murine tumor models, except for a few studies exploring combination treatments (Lhuillier et al., 2021; Jagodinsky et al., 2022). Radiotherapy has the potential to serve as an important adjunct to immunotherapy by triggering several elements of the immune system, particularly through enhancing antigen recognition and boosting T cell activity. Future research should focus on optimizing treatment strategies by combining radiotherapy with ICIs, cytokine therapies, and DNA damage response inhibitors, as well as overcoming immune evasion mechanisms, T cell exhaustion and insufficient T-cell infiltration to improve the cooperative effects of radiotherapy and immunotherapy.

IR-induced immunosuppression, which includes combining host cell-extrinsic effects and tumor cell-intrinsic resistance, may contribute to certain therapy failures (Wang et al., 2024). Kenneth K et al. first discovered that postmastectomy radiation in breast cancer patients leads to a reduction in lymphocyte counts, potentially impairing cellular immunity (Meyer, 1970). Accumulating evidence suggests that myeloid subpopulations remain a significant challenge in radiotherapy (Kleinberg et al., 2019; Pham et al., 2023). Tregs are a distinct subset of CD4+ T cells defined by the overexpression of Forkhead box P3 (FoxP3) and CD25. IR significantly increases the infiltration of Tregs into tumors in differing murine neoplasm models, including melanoma, B cell lymphoma, and prostate cancer (Dutt et al., 2018; Kachikwu et al., 2011). Numerous clinical investigations indicate that radiotherapy, encompassing chemo-radiotherapy or SBRT, elevates the levels of circulating Tregs in the peripheral blood mononuclear cells of patients undergoing treatment for diverse malignancies (Wang et al., 2024).

Subhajit Ghosh et al. reported that IR can markedly elevate circulating MDSCs in humans and various murine models such as hepatocellular carcinoma (HCC), lung cancer melanoma etc (Ghosh et al., 2023). Radiotherapy induces MDSCs in various organs (spleen, peripheral blood, lung, and lymph nodes), contributing to suboptimal antineoplastic effects (Xu et al., 2013). Prior research has shown that activation of the cGAS-STING pathway in MDSCs serves a crucial function in recruiting monocyte-type MDSCs through a CCR2-dependent mechanism within a colon cancer model (Yang et al., 2020b). The CSF1/CSF1R, HIF-1α/STAT3, YTHDF2/NF-κB signal pathways have close relationships with IR-induced MDSC tumor infiltration (Liang et al., 2017; Wang-Bishop et al., 2023). TAMs are involved in various essential stages of tumorigenesis, such as angiogenesis, inhibition of adaptive immune responses, and formation of the premetastatic niche.

Macrophages were categorised into M1 (anti-tumorigenic) and M2 (pro-tumorigenic) categories, with evidence suggesting that radiotherapy may elicit an M1-like behaviour characterized by elevated expression of inducible nitric oxide synthase, while M2-like macrophages display higher radio-resistance (Teresa Pinto et al., 2016). Radiotherapy also impacts immune evasion mechanisms within the TME. Tumor cells can express immune checkpoint molecules (PD-L1 and CTLA-4 etc.), which inhibit T cell function, leading to rapid T cell exhaustion (Gough and Crittenden, 2022). The expanding number of preclinical and clinical evidence on the combination of RT with immunomodulators, demonstrates the considerable interest of the scientific and medical world about immune-radiotherapy (Wang et al., 2024; Mondini et al., 2020). Therefore, while radiotherapy activates immune responses, these responses are often limited by immune suppressive factors in the TME, necessitating the use of combination immunotherapy strategies to overcome this limitation.

In the TIME, mitophagy plays a crucial dual role between immune suppression and immune activation. In immune-activating microenvironments, such as anti-tumor immune responses or immune inflammation, immune cells like macrophages, B cells, NK cells, and CD8+ T cells rely on abundant energy to perform their immune functions (Xu et al., 2014; Chen et al., 2014). Mitophagy provides sufficient energy to support antigen presentation, cytokine secretion, and cell proliferation during immune responses. Specifically, mitophagy enables DCs to more effectively present antigens and trigger naïve T cell reactions. Macrophages also regulate their mitochondrial function to enhance phagocytosis and microbial killing, thereby boosting immune defense (Larson-Casey et al., 2016). Moreover, immune cells undergo metabolic reprogramming when encountering pathogens or tumors, with mitophagy playing a crucial role in this process. For example, activated T cells increase OXPHOS to supply energy, and mitophagy helps regulate this process, preventing metabolic overload, ensuring that immune cells maintain effective functions.

In immunosuppressive microenvironments, tumor cells enhance mitophagy to clear damaged mitochondria, thereby reducing energy consumption and ROS generation, maintaining metabolic balance, and preventing excessive immune responses (Kowluru and Alka, 2023). This mechanism not only helps tumor cells evade immune surveillance but also promotes immune suppression by modulating the metabolism of TAMs to an M2 polarization state. Additionally, mitophagy inhibits the metabolic processes of DCs and effector T cells, impairing their anti-tumor functions and leading to immune tolerance (Wu et al., 2023). The antigen-presenting capacity of DCs is suppressed, and the activity and proliferation of effector T cells are constrained, consequently, the anti-tumor immunological function is inhibited. Considering the dual function of mitophagy in the IME, targeting its regulation presents a promising therapeutic strategy. In immunosuppressive microenvironments, inhibiting mitophagy may aid in improving anti-tumor immune responses and overcoming tumour immune evasion. In immune-activating microenvironments, enhancing mitophagy could improve immune cell function and increase the efficiency and sustainability of immune responses. This provides a promising direction for mitophagy as a therapeutic target.

In recent years, increasing evidence has highlighted the complex interplay between diabetes and cancer therapy resistance, particularly through mechanisms involving mitophagy, modulation of the TME, and radioresistance. Diabetes is characterized by chronic inflammation and metabolic dysregulation, which are known to disrupt mitochondrial function and immune homeostasis. Type 1 diabetes is the predominant form of diabetes in pediatric populations, with approximately 100,000 new cases diagnosed in children each year. Insulin serves as the first-line treatment (Patterson et al., 2019). A study on type 1 diabetes demonstrated that mitochondrial dysfunction, induced by hyperglycemia, leads to the release of mtDNA and ROS, which subsequently trigger pro-inflammatory signaling pathways and exacerbate autoimmune responses against pancreatic β-cells (Blagov et al., 2023). Our review focus on the discussion of T2DM research. Under hyperglycemic conditions, β-cells in T2DM undergo mitochondrial structural and functional dysregulation, characterized by enhanced fission, reduced fusion, and impaired mitophagy, ultimately exacerbating cellular damage and β-cell dysfunction (Shan et al., 2022). Concomitantly, patients with T2DM exhibit downregulation of key mitophagy-associated genes, including NIX, PINK1, and Parkin (Scheele et al., 2007a). More abnormal mitochondria were observed in T2DM patients with the smaller size of mitochondria as well as swollen and disrupted mitochondria in the hepatocytes from insulin-resistant patients (Scheele et al., 2007b; Bhansali et al., 2017). Excessive mitochondrial ROS from dysfunctional mitochondria induces β-cell apoptosis and exacerbates insulin resistance (Hou et al., 2008). In the past decade, alterations in autophagy have been shown to play a fundamental role in the development and control of T2DM (Apostolova et al., 2023). In the context of diabetes, mitophagy is primarily regulated through two classical pathways: the PINK1/Parkin-dependent pathway and the receptor/adaptor-mediated pathway involving proteins such as BNIP3, NIX, and FUNDC1, along with ubiquitin-binding adaptors including p62 and OPTN. However, in diabetic conditions, the activity of these pathways may be impaired, leading to reduced mitophagy and accumulation of dysfunctional mitochondria (Narendra et al., 2008a; Unoki and Nakamura, 2001; McWilliams and Muqit, 2017; Jin et al., 2010; Deas et al., 2011; Eldeeb and Ragheb, 2020; Wu et al., 2016; Tang et al., 2024).

In T2DM, chronic hyperglycemia and insulin resistance induce low-grade systemic inflammation, which is exacerbated by defective autophagic processes (Saltiel and Olefsky, 2017). Impaired autophagy in immune cells—such as macrophages, DCs, and T lymphocytes—leads to dysregulated cytokine production (IL-1β, IL-18 etc.), decreasing of antigen presentation, immune evasion and radioresistance. Islet sections from T2DM pancreata exhibit significantly increased macrophage presence compared to non-diabetic controls (Kattner, 2023). Recent studies have demonstrated that defective mitophagy skews macrophage polarization toward the pro-inflammatory M1 phenotype, promotes NLRP3 inflammasome activation, and impairs Tregs function (Choudhuri et al., 2021; Xu et al., 2020). Conversely, insulin therapy in T2DM patients is associated with an anti-inflammatory immune profile, characterized by the differentiation of CD4+ T helper cells into IL-10-producing effector T cells, with concomitant increases in Treg and B cell populations (Nekoua et al., 2016). Collectively, these immune dysregulations and autophagy impairments sustain a pro-inflammatory microenvironment that exacerbates insulin resistance and β-cell dysfunction. Importantly, selective autophagy processes such as mitophagy mitigate mitochondrial ROS accumulation and inflammasome activation, underscoring a critical mechanistic link between mitochondrial quality control and immune homeostasis in T2DM. These findings suggest that diabetes-associated mitochondrial stress may contribute to altered immune surveillance in the tumor microenvironment. Restoration of autophagic flux through pharmacological or genetic interventions thus represents a promising strategy to reprogram the immune microenvironment and alleviate metabolic inflammation in T2DM.

In the context of diabetes, insulin resistance and metabolic reprogramming caused by persistent hyperglycemia may further aggravate radioresistance. Emerging studies indicate that RT can activate the immune system by inducing immunogenic cell death and releasing tumor-associated antigens, but diabetes-related metabolic abnormalities may weaken this immune activation effect (Liu et al., 2024). Furthermore, radiation-induced systemic immune activation, which is partially driven by cytosolic mtDNA, may be attenuated by autophagic degradation of mitochondrial contents—an effect that could be enhanced under diabetic conditions (Yamazaki et al., 2020; Mitrofanova et al., 2022). Diabetes-induced metabolic reprogramming contributes to an immunosuppressive TME by accumulating lactate, which impairs the function of effector T cells and NK cells, while promoting the Tregs expansion and M2-type TAMs (Brand et al., 2016). Concurrently, alterations in lipid metabolism enhance fatty acid oxidation in tumor cells, providing additional energy to support their survival post-radiotherapy. This metabolic shift also facilitates the upregulation of "don't eat me" signals, such as CD47, thereby evading immune cell clearance and enhancing radioresistance (Jiang et al., 2022; Park et al., 2016). Furthermore, chronic inflammation and metabolic disturbances associated with diabetes may upregulate immune checkpoint molecules like PD-L1, further suppressing T cell activity and diminishing the efficacy of radiotherapy (Ricci, 2025). Collectively, these mechanisms synergistically contribute to increased radioresistance in diabetic patients.

T2DM has several epidemiological, genetic, and metabolic similarities that indicate a bidirectional link the two diseases (Giovannucci et al., 2010). Epidemiological studies have demonstrated that patients with T2DM exhibit a 20–50 % elevated risk of acquiring several malignancies, such as liver, pancreatic, colorectal, and endometrial cancers (Pearson-Stuttard et al., 2018; Zhang et al., 2021). Conversely, the presence of certain cancers may provoke metabolic dysregulation, leading to insulin resistance and hyperglycemia (Pearson-Stuttard et al., 2018). Both T2DM and cancer are characterized by chronic low-grade inflammation, hyperinsulinemia, and altered glucose metabolism (Balkwill and Mantovani, 2001). Insulin and insulin like growth factor (IGF) signaling pathways, frequently increased in T2DM, are crucial facilitators of cancer, enhancing cell proliferation and suppressing apoptosis (Pollak, 2008). A shared molecular hallmark of both diseases is mitochondrial dysfunction, particularly in the form of impaired mitophagy, the selective autophagic clearance of damaged mitochondria. In T2DM, impaired mitophagy leads to the accumulation of dysfunctional mitochondria, aggravating oxidative stress and insulin resistance (Zong et al., 2016). In cancer, compromised mitophagy facilitates tumor survival during metabolic stress and enhances treatment resistance (Memon et al., 2022). Therefore, the relationship between metabolic reprogramming and mitophagy failure provides new understandingof the pathophysiology of malignancieslinked to T2DM and identifies possible targets for co-treatment approaches.

Mitophagy activators such as rapamycin, metformin, and urolithin A are emerging as promising agents that enhance mitochondrial turnover, which is critical for immune cell function, especially during radiotherapy and immunotherapy. Their ability to modulate mitochondrial health provides an advantage in cancer treatment. Mitophagy inhibitors, such as Verapamil and Bafilomycin A1, play a role in sensitizing tumors to radiotherapy by inhibiting mitochondrial fusion and clearance. These inhibitors can disrupt tumor cell survival mechanisms, enhancing the effectiveness of radiotherapy. The co-administration of mitophagy modulation with immunotherapy, including CAR-T cell therapy and checkpoint-targeting antibodies (such as nivolumab and ipilimumab), shows significant promise in overcoming immune suppression in tumors and enhancing anti-tumor immune responses (Table 1).

Targeted mitophagy is emerging as a potential approach for the treatment of cancer since it can selectively eliminate dysfunctional mitochondria, thus reprogramming cellular metabolism and mitigating cancer progression. However, its clinical application faces several challenges and risks of side effects. One major concern is the possibility of exacerbating cancer cell survival under hypoxic and nutrient-deprived TME (Panigrahi et al., 2020). Cancer cells often exploit mitophagy to adapt to stress conditions, enhancing tumor tolerance to therapies such as chemotherapy and radiation. Overactivation of mitophagy may therefore inadvertently enhance tumor resilience and metastasis (Jin et al., 2022). Additionally, targeting mitophagy may disrupt the immune response. Proper mitochondrial dynamics are necessary for the key immune cells activation, including T cells and macrophages. Excessive mitophagy induction may impair antigen presentation, cytokine production, and immune surveillance, undermining anti-tumor immunity. This poses a particular challenge when combining mitophagy-targeting agents with immunotherapies (Ikeda et al., 2025; Chen et al., 2024).

Another significant challenge is the lack of selectivity in mitophagy-targeting drugs. Numerous currently available agents—including mitochondrial uncouplers and PINK1-Parkin pathway activators—impact both normal and malignant cells. This dual effect may cause toxicity in healthy tissues with high mitochondrial requirements, like the brain and heart (Shrestha et al., 2021; Ivankovic et al., 2016). Recent discussions highlight the necessity for more sophisticated approaches, such as tumor-specific delivery systems and the development of mitophagy inhibitors that selectively modulate the mitochondrial quality control pathways in cancer cells. The integration of advanced nanotechnology and genetic engineering may offer promising solutions (Surnar et al., 2018; Yao et al., 2022). Furthermore, clinical translation is hampered by limited biomarkers to monitor mitophagy dynamics in real time. Accurate and reliable detection methods are crucial for patient stratification and response evaluation. As research advances, multi-omics profiling and non-invasive imaging technologies are expected to play critical roles in overcoming these hurdles (Li et al., 2021). A balanced and targeted modulation of mitophagy, considering tumor type and immune microenvironment context, continues to be crucial for its effective clinical use.

RT alters homeostasis and cell distribution within the TME. Although the combining radiotherapy with immunotherapy offers a novel strategy for anti-tumor treatment, its efficacy still faces numerous challenges and limitations. Potential of targeting mitophagy in combination with novel immunotherapies, such as CAR-T cell therapy and bispecific antibodies, presents an encouraging therapeutic tactic in oncological treatment (Li et al., 2025). Recent studies suggest that modulating mitophagy can alter the TIME, potentially augmenting the impact of immunotherapies (Behera et al., 2025). CAR T-cell therapy research and development has advanced through insights gained from laboratory studies and clinical trials involving lymphokine-activated killer cells, tumor-associated lymphocytes, and allogeneic hematopoietic stem-cell transplantation for cancer therapy. The study still lacks sufficient experimental data on CAR-T combined with mitochondrial autophagy regulators. The targeting mitophagy may improve T cell persistence and function by ensuring proper mitochondrial function, which is crucial for T cell activation and longevity. Furthermore, inhibiting mitophagy in tumor cells could sensitize them to immune attack by preventing the escape mechanisms that tumors utilize to evade immune surveillance. Besides, some bispecific antibodies, designed to redirect immune effector cells to tumor cells, may also benefit from mitophagy modulation by enhancing the immune