Malignant tumors, which are characterized by
phenotypic plasticity, metabolic reprogramming and immune evasion,
continuously adapt to conventional treatment strategies,
highlighting the urgent need for the development of novel and more
effective therapeutic approaches (1). Radiotherapy exerts its tumor-killing
effects through two main mechanisms: i) Direct DNA damage induced
by high-energy radiation; and ii) indirect DNA damage via reactive
oxygen species (ROS). Ionizing radiation (IR) releases high-energy
photons that disrupt the DNA structure of tumor cells, leading to
base modifications and single- or double-strand breaks. These DNA
lesions result in cell cycle arrest, apoptosis or necrosis,
directly impacting tumor cell survival (2). In addition to DNA damage, IR induces
the decomposition of intracellular water, generating substantial
hydroxyl radicals (OH·) and other ROS species. IR causes a redox
imbalance within cells, which leads to lipid peroxidation, protein
denaturation and DNA damage, further disrupting normal cellular
processes, particularly mitochondrial function (3). With advancements in computational
modeling, image-guided technologies and biochemical agents,
radiotherapy has been increasingly optimized and currently
demonstrates distinct advantages in combination with other
therapies. While previous studies have primarily focused on the
mechanisms underlying DNA damage from radiotherapy (4,5),
recent research on tumor hypoxia and metabolic reprogramming has
shifted attention toward ROS-induced damage and mitochondrial
dysfunction resulting from redox imbalance, which have become key
areas of investigation (6,7).
Ferroptosis is a newly identified form of programmed
cell death characterized by iron-dependent lipid peroxidation,
accompanied by an immunogenic response. This form of cell death is
intricately linked to the cellular metabolic state and redox
balance, serving a critical role in the regulation of radiotherapy
efficacy (8). IR promotes the
generation of ROS, which directly damage nucleic acids and lipids
in tumor cells, thereby triggering lipid peroxidation and
ferroptosis (9). In the context
of therapeutic resistance, particularly in chemotherapy,
radiotherapy and immunotherapy, tumor cells (and especially those
in a mesenchymal state with higher metastatic potential) become
more susceptible to ferroptosis due to mitochondrial metabolic
alterations dependent on the tumor microenvironment (TME) (10). Ferroptosis emerges as a promising
pathway for enhancing radiation sensitivity, facilitated by the
combined effects of mitochondrial-mediated redox reactions, lipid
peroxidation and dysregulated iron metabolism. This offers notable
clinical potential for overcoming resistance to conventional
therapies (11,12).
Mitochondria are not only the powerhouse of the cell
but also central hubs for redox reactions, iron metabolism and
lipid peroxidation (13).
Mitochondrial involvement in ferroptosis extends beyond regulating
redox imbalance, as they are also crucial in ROS accumulation
(14). As a result, mitochondria
serve a pivotal role in maintaining intracellular redox equilibrium
and are essential for executing ferroptotic cell death. In the
context of radiotherapy, mitochondrial dysfunction and redox
imbalance further drive ferroptosis, while the immunogenic response
triggered by ferroptosis provides new opportunities for enhancing
radioimmunotherapy. Ferroptosis is not merely a form of cell death;
it elicits an immune response that activates immune cells within
the TME, thereby improving the therapeutic efficacy of radiotherapy
(15).
Despite these findings, the reciprocal regulatory
mechanisms between mitochondria and ferroptosis, as well as the
associated immune activation in the context of radiotherapy, remain
incompletely understood. As research into the association between
mitochondria and ferroptosis advances, targeting mitochondrial
ferroptosis may become a key strategy for radiation
immunosensitization. The present review explored the mechanisms
underlying the interaction between ferroptosis and mitochondria
under IR, and discussed the potential for targeting mitochondrial
ferroptosis as a strategy for enhancing radioimmunotherapy, aiming
to uncover the clinical importance of mitochondrial ferroptosis in
radiation-based cancer treatment.
The incidence and mortality rates of cancer continue
to rise, and radiotherapy, a cornerstone in cancer treatment, has
been developed and use in the clinic for >100 years (16). Several common cancer types,
including nasopharyngeal carcinoma and esophageal cancer, can be
effectively treated with radiotherapy, either as a monotherapy or
in combination with chemotherapy, immunotherapy and
targeted-therapy (17). However,
a subset of patients still experiences recurrence or metastasis,
presenting a persistent challenge to the efficacy of clinical
radiotherapy. Radiotherapy dosage is a crucial determinant of tumor
control rates; however, high radiation doses may lead to
significant damage to surrounding normal tissues and organs.
Therefore, optimizing the radiation dose, enhancing tumor
radiosensitivity and minimizing toxic side effects remain critical
challenges yet unresolved in the field of radiotherapy (18,19).
Previous research has indicated that the primary
mechanism of tumor cell death induced by radiotherapy is through
IR-induced proliferative cell death, which includes apoptosis,
autophagy and necrosis (20).
However, increasing attention has been paid to the potential role
of other forms of regulated cell death (RCD) in radiotherapy's
therapeutic effects (21,22). Ferroptosis, a form of
radiation-induced cell death, has emerged as an important
contributor to tumor response, and exhibits characteristics of ICD,
which is intricately linked with radioimmunotherapy (23). The hallmark of ferroptosis is
iron-dependent lipid peroxidation, particularly of polyunsaturated
fatty acid (PUFA)-phospholipids (PLs), accompanied by
characteristic mitochondrial morphological changes such as
shrinkage, loss or reduction of mitochondrial cristae and increased
mitochondrial membrane density. In the context of radiotherapy, IR
induces immune system recognition and activation by releasing
specific immune stimulants, such as High Mobility Group Box 1
Protein (HMGB1, a nuclear protein promotes late-stage
inflammation), ATP and exposed cell membrane antigens, thus
triggering ICD and activating CD8+ T cells. IFN-γ
produced by CD8+ T cells can alter the lipid metabolic
profile of tumor cells, promoting ferroptosis through an
ACSL4-dependent pathway (24).
Notably, ferroptosis exhibits crosstalk with various
forms of RCD, particularly under oxidative stress conditions, a
hallmark of radiation exposure. NADPH oxidase (NOX), a key
regulator of lipid redox signaling, serves dual roles in both
apoptotic pathways and ferroptosis initiation through lipid
peroxidation induction (25).
During bortezomib-induced apoptosis, ACSL4 inactivation may
suppress the incorporation of PUFAs into cell membranes,
consequently diminishing ferroptotic susceptibility. Furthermore,
selective autophagy-mediated GPX4 degradation results in
intracellular accumulation of free iron and lipid peroxides,
ultimately driving ferroptosis progression (26,27).
Radiation-induced ferroptosis not only interacts
with other RCD mechanisms, such as apoptosis and autophagy, to
modulate tumor cell radiosensitivity, but also reshapes the TME by
enhancing the activation and infiltration of immune cells (28). This immune activation, in turn,
further sensitizes the tumor to radiotherapy, especially in
radioimmunotherapy strategies (28). Specifically, radiotherapy-induced
ferroptosis enhances the uptake of tumor antigens by dendritic
cells (DCs), thus boosting tumor-specific T cell responses.
Additionally, ferroptosis can modulate the activity of
myeloid-derived suppressor cells (MDSCs) and regulatory T cells
(Tregs), thus reshaping the immune landscape of the TME and
preventing immune escape (29).
Research into the regulatory pathways of ferroptosis
has identified several defense systems with distinct subcellular
localizations, including Solute Carrier Family 7 Member 11
(SLC7A11, an antiporter that imports cystine for glutathione
synthesis)-glutathione (GSH)-glutathione peroxidase 4 (GPX4),
NAD(P)H-FSP1-CoQ, GCH1-BH4-DHFR, sex hormone-MBOAT1/2 and
mitochondrial-localized dihydroorotate dehydrogenase
(DHODH)-CoQH2 (30).
These defense systems regulate key processes such as iron
metabolism, redox balance and lipid peroxidation in different
cellular compartments, collectively maintaining cellular
homeostasis (Fig. 1). When these
defense mechanisms are disrupted, cells become more vulnerable to
ferroptosis, particularly metabolically active tumor cells
(31). Inhibiting key antioxidant
enzymes and iron homeostasis regulators can significantly enhance
the efficacy of radiotherapy. Consequently, targeting the
ferroptosis defense systems has emerged as an effective strategy
for radiosensitization in malignant tumors.
Mitochondria are dynamic organelles with a
double-membrane structure, serving a pivotal role in maintaining
cellular homeostasis through multiple pathways, including the
kallikrein system, the unfolded protein response, autophagy and
various metabolic processes (32). However, common mitochondrial
defects in tumor cells can significantly alter energy production,
shifting from oxidative phosphorylation (OXPHOS) to a more
simplified, oxygen-independent glycolysis pathway, in order to meet
the high metabolic demands of rapid proliferation and the hypoxic,
acidic microenvironment typical of tumors (33). These mitochondrial defects also
downregulate the mitochondrial apoptosis pathway, a key factor that
enables tumor cells to sustain their malignant phenotype and
develop resistance to radiation. IR induces serious damage to the
mitochondrial membrane, altering its permeability and leading to
mitochondrial swelling, vacuolization and fragmentation of the
cristae. The damage impairs the electron transport chain (ETC) and
results in ROS accumulation (34). The dysfunction of mitochondria
caused by IR can be further amplified through mitochondrial fusion
and fission processes, which help dilute the damaged mitochondria.
This leads to the genetic transmission of oxidative stress damage
within the cell, causing side effects, exacerbating instability in
both mitochondrial and nuclear DNA (35). In response to IR, tumor cells
compensate by increasing the number of mitochondria and activating
repair mechanisms to offset declines in mitochondrial respiratory
efficiency, partially restoring mitochondrial function after
IR-induced damage (36). However,
this compensatory response leads to sustained ROS production,
excessive depletion of mitochondrial antioxidants such as manganese
superoxide dismutase and coenzyme Q, which further aggravates
mitochondrial damage and generates more ROS, creating a vicious
cycle that increases the risk of cell death (37).
In a microenvironment with persistently high ROS
levels, tumor cells undergo long-term damage, leading to cellular
senescence after repeated irradiation and exacerbating secondary
radiation damage (38).
Mitochondria play a critical role in cellular metabolic plasticity
and regulate various forms of RCD, including ferroptosis, following
radiation injury. Irreversible mitochondrial outer membrane
permeabilization (MOMP) results in the release of pro-apoptotic
factors such as cytochrome c from the intermembrane space
into the cytoplasm, which activates the caspase-9-dependent
intrinsic apoptosis pathway (39). Furthermore, mitochondrial DNA
(mtDNA) released into the cytoplasm is recognized by cyclic GMP-AMP
synthase (cGAS), which activates the cGAS-STING inflammatory
pathway, triggering pyroptosis and inhibiting mitochondrial
autophagy, thereby exacerbating mitochondrial damage (40). In addition to acting as a
cytoplasmic DNA sensor that activates innate immune responses, cGAS
also contains a mitochondrial targeting sequence, enabling its
localization to the mitochondrial outer membrane (OMM), where it
plays a protective role against ferroptosis (41). As IR intensifies its effects on
mitochondrial function in tumor cells, structural and metabolic
alterations in mitochondria significantly enhance ferroptosis,
supporting the potential of ferroptosis in radioimmunotherapy
strategies.
Mitophagy, a selective form of macroautophagy that
induces the degradation of dysfunctional and damaged mitochondria
via the autophagy pathway. Mitophagy serves a key role in
maintaining cellular homeostasis (42). Protein disulfide isomerase (PDI),
an enzyme primarily located in the endoplasmic reticulum (ER),
mediates disulfide bond formation and is often highly expressed in
tumor tissues, where its elevated levels correlate with increased
pathological grading (43). In
colorectal cancer (CRC) cells subjected to radiation-induced ER
stress, PDI not only inhibits autophagy initiation by activating
the GRP78-mTOR pathway but also competes with LC3Ⅱ for binding to
the mitochondrial autophagy receptor PHB2, thereby regulating the
mitophagy process and reducing radiation sensitivity (44). Specifically, PDI plays a critical
role in balancing ferroptosis and mitophagy. During ferroptosis,
PDI modulates cellular iron homeostasis and redox reactions by
influencing antioxidant activity. Additionally, through its dual
localization in both the ER and mitochondria, PDI regulates the ER
stress response and impacts mitophagy initiation by interacting
with PHB2 (44). Through these
mechanisms, PDI not only suppresses autophagy initiation but also
plays a pivotal role in regulating ferroptosis.
Functionally intact and structurally complete
mitochondria are crucial in defending against ferroptosis through
various metabolic and antioxidant pathways (45). On the OMM, voltage-dependent anion
channels (VDAC) 2/3, iron transporter proteins Mfrn1/Mfrn2, the
mitochondrial permeability transition pore and the mitochondrial
Ca2+ uniporter facilitate the physiological uptake of
Fe2+, maintaining a labile iron pool (46). Mitochondrial ferritin (FtMt) plays
a pivotal role in regulating iron metabolism within the
mitochondrial matrix. It is involved in the synthesis of
iron-sulfur (Fe/S) cluster proteins, such as NADH dehydrogenase,
cytochrome c and succinate dehydrogenase, thereby
maintaining ATP production and preventing the accumulation of
mitochondrial ROS (mtROS) (47).
FtMt also regulates the availability of free iron in mitochondria,
mitigating iron overload, oxidative stress and ferroptosis under
conditions such as cerebral ischemia-reperfusion and IR injury. The
Fe/S cluster proteins mitoNEET and frataxin on the OMM are
similarly essential for maintaining mitochondrial iron metabolism
balance and inhibiting ferroptosis. In addition to iron metabolism,
cellular energy metabolic pathways, including the tricarboxylic
acid cycle (TCA) and OXPHOS, as well as associated regulatory
factors such as NADPH, GSH and AMPK, all play critical roles in
ferroptosis regulation (48). For
example, the mitochondrial transmembrane protein MTCH1 stabilizes
the mitochondrial OXPHOS cycle and mtROS levels; its deficiency
activates pro-ferroptotic retrograde signaling involving the
FoxO1-GPX4 axis, which synergistically enhances the antitumor
activity of ferroptosis-inducing agents such as sorafenib (49).
Mitochondrial cysteine metabolism also plays a
central role in ferroptosis regulation. The cysteine desulfurase
complex NFS1-ISD11 provides sulfur for Fe-S cluster formation and
promotes GSH synthesis, thus upregulating the activity of the
GSH-GPX4 antioxidant system (50). The hereditary inactivation of
fumarase, a key enzyme in the TCA cycle, induces ferroptosis by
downregulating GPX4 activity in conditions such as smooth muscle
tumors and renal cell carcinoma (51). NADPH, which is critical for GSH
conversion in the mitochondrial TCA cycle, is catalyzed by
NADP+-dependent isocitrate dehydrogenase (IDH), and its
cytoplasmic source can be provided by the reversible oxidative
decarboxylation of malate to pyruvate catalyzed by malic enzyme 1
(ME1). NADPH not only drives ATP release through coupling with
OXPHOS but also maintains the GSH cycle across various metabolic
pathways, thus counteracting mitochondrial lipid peroxidation and
reducing susceptibility to ferroptosis (51).
The ETC complexes (complexes I-IV) and ATP synthase
(complex V) stimulate ATP synthesis through phosphocreatine and
activate the AMPK signaling pathway. Inhibiting acetyl-CoA
carboxylase phosphorylation and PUFA synthesis also negatively
regulates mitochondrial ferroptosis, exerting similar effects to
those of the LKB1-AMPK axis (52). Similarly, enzymes targeting
mitochondrial CoQ reduction, such as DHODH and G3P dehydrogenase 2
(GPD2), inhibit mitochondrial lipid peroxidation and ferroptosis by
reducing CoQ to CoQH2 (53). GPD2 further synergizes with
mtGPX4, leading to the acetylation of mtGPX4 and contributing to
cadmium-induced renal cell ferroptosis (54). The role of mitochondrial
supercomplexes formation and its regulatory factor COX7A2L in
ferroptosis sensitivity has also been confirmed (55). COX7A2L deficiency induces
mitochondrial metabolic reprogramming, enhancing glutamine (GLN)
metabolism, cell proliferation and oxidative defense against
ferroptosis (56). Furthermore,
several regulatory factors that are localized in or translocated to
mitochondria after activation also serve a key role in
mitochondrial ferroptosis. Mitochondrial inner membrane-localized
PDK4 inhibits ferroptosis by blocking pyruvate
dehydrogenase-dependent pyruvate oxidation and fatty acid
synthesis. However, the roles of AMPK and PDK4 in ferroptosis are
cell-type-dependent, with complex interactions between energy
status and ferroptosis induced by different activators (57). The mitochondrial metabolic enzyme
PCK2 phosphorylates ACSL4 and promotes ACSL4-associated PL
remodeling in tumor cells. Cancer stem cells promote PCK2
ubiquitination and degradation, thus maintaining membrane PLs in a
ferroptosis-tolerant state (58).
Activated by PLC kinase, monocarboxylate transporter 1 (MCT1)
translocates to the mitochondrial surface, mediating lactate
uptake, promoting ATP production and inactivating AMPK, which
increases the expression of sterol regulatory element-binding
protein 1, stearoyl-CoA desaturase 1 and the end products
monounsaturated fatty acids, thereby contributing to ferroptosis
resistance (59). Furthermore,
lithium carbonate-induced MCT1 translocation and Ca2+
release activate LA oxidation in mitochondria, reactivating
LA-suppressive CD8+ T effector cells (60). Mitochondria serve a key role in
cysteine deprivation-induced (CDI) ferroptosis, which is distinct
from GPX4 inhibition-induced ferroptosis, with the TCA cycle and
amino acid metabolism pathways closely linked to CDI ferroptosis
(61). GLN, a key respiratory
substrate for energy production and lipid synthesis in tumor cells,
is degraded by mitochondrial glutaminases (GLS) 1/2. Due to their
similar amino acid sequences encoded by unrelated genes, reduction
of GLS2, rather than GLS1, through genetic or pharmacological
mechanisms, inhibits CDI ferroptosis. Aminooxyacetate inhibits the
conversion of GLN to α-ketoglutarate, rescuing CDI ferroptosis in
tumor cells (61).
Mitochondria-associated ER membranes (MAMs) are
highly dynamic and tightly interconnected structures between the
mitochondria and the ER. MAMs serve as a platform for
Ca2+ signaling between the two organelles and serve a
vital role in regulating mitochondrial ferroptosis signaling
(62). Mitochondrial microsomal
glutathione S-transferase 1 limits lipid peroxidation and
ferroptosis by binding to and downregulating ALOX5 activity
(63). The calcium-sensitive
receptor chaperone protein σ1R mediates the inhibitory effect of
the kinase inhibitor CGI1746 on ferroptosis. CGI1746 also slows the
Ca2+ transport rate within MAMs, disrupting the
ferroptosis process (64). The
IP3R-GRP75-VDAC1 axis is a key regulatory pathway for the dynamic
changes in MAMs, and its inhibition leads to the accumulation of
PUFA-containing triacylglycerols, conferring resistance to
ferroptosis (65). Mitofusin-2
(Mfn-2), originating from both the mitochondrial membrane and the
ER surface, mediates physical and biochemical interactions between
the mitochondria and the ER. Mfn-2 serves a key role in
mitochondrial fusion and stabilizing mitochondrial-ER contact sites
(66). Mfn-2 interacts with the
ER-resident protein inositol-requiring enzyme 1α (IRE1α) to
participate in arsenic-induced ferroptosis, while IRE1α also
influences ferroptosis sensitivity by regulating GSH synthesis
(67). Deficiency in the
autophagy regulator WIPI4 increases the localization of ATG2 to
mitochondria and MAMs, which enhances the transfer of
phosphatidylserine within MAMs and the ATG2-dependent synthesis of
mitochondrial phosphatidylethanolamine (PE) by phosphatidylserine
decarboxylase (PISD), ultimately triggering mitochondrial membrane
lipid peroxidation and ferroptosis (68). Inhibition of PISD protects cells
from ferroptosis induced by WIPI4 depletion and other inducers,
suggesting that PE synthesis in mitochondria may represent a
general early step in ferroptosis (69).
The regulatory role of mitochondrial metabolic
pathways in ferroptosis varies across different tumor types
(70). For instance, abnormal
NADPH production and regulation may result in notable differences
in ferroptotic effects across malignancies (71). Enzymes involved in NADPH
production, such as IDH and ME1, exhibit mutations or deletions in
different cancer types, leading to an imbalance in the antioxidant
system (72). Specifically, in
cholangiocarcinoma, IDH1 mutations promote ferroptosis by lowering
GPX4 expression and accelerating GSH depletion (73). In synovial sarcoma, ME1 deficiency
alters the mitochondrial NADPH-dependent antioxidant system,
increasing susceptibility to ferroptosis induced by ACXT-3102
(74). MAMs also display
different ferroptosis sensitivities under various treatments within
the same tissue type. mtROS activate the PERK pathway, suppress
Mfn-2 expression and cause MAM dysfunction, contributing to
arsenic-induced ferroptosis in liver cells. Upregulation of PERK-c
fragment expression in MAMs can trigger alcoholic liver
ferroptosis, a process inhibited by quercetin (75). Thus, research into mitochondrial
metabolic pathways and MAMs regulatory mechanisms across tumor
types could offer novel insights into their susceptibility and
resistance to ferroptosis, providing potential therapeutic targets
for clinical treatment.
Overall, the regulatory role of mitochondria in
ferroptosis encompasses iron metabolism, energy metabolism,
antioxidant regulation and transmembrane signaling with the ER.
These pathways and mechanisms exhibit marked variability across
different tumor types. A deeper understanding of these differences
could provide personalized therapeutic strategies for
ferroptosis-related anticancer treatments.
IR induces ferroptosis in tumor cells through
multiple mechanisms, which is closely tied to mitochondrial
metabolic reprogramming (15).
Upon exposure to IR, mitochondria in tumor cells undergo shrinkage
and vacuolization, while key components of the cysteine/glutamate
antiporter system (system XC-), including SLC3A2 and SLC7A11, are
significantly downregulated. This downregulation reduces the
synthesis of mtGPX4, thereby weakening the mitochondria's ability
to counter lipid peroxidation (76). IR also enhances tumor cell glucose
and GLN metabolism, dose-dependently increasing ROS production,
which leads to mitochondrial energy stress. In addition, IR
upregulates the expression of the iron transporter SLC39A14 and the
key enzyme ACSL4, which is involved in PUFA-PLs metabolism, thus
inducing lipid peroxidation (77). Furthermore, a reduction in
mitochondrial membrane potential and the proteolytic cleavage of
PTEN-induced kinase 1 (PINK1) by the inner membrane protease,
presenilin-associated rhomboid-like protease, leads to the
stabilization of full-length PINK1 on the OMM. This stabilization
recruits the E3 ubiquitin ligase Parkin from the cytoplasm,
promoting the ubiquitination of OMM proteins, including VDAC1 and
mitochondrial fusion proteins, Mfn-1/2. p62 is subsequently
recruited to the mitochondrial surface, initiating mitophagy
(78). Lipid droplets (LDs),
which serve as cellular organelles for fatty acid storage, are
degraded by lysosomes via autophagy under radiation stress,
increasing the release of free fatty acids (FFAs) and the risk of
lipid peroxidation (79). IR also
induces an increase in LD volume and their proximity to
mitochondria, eventually forming mitochondrial-LD complexes that
facilitate fatty acid transfer to mitochondria (80,81). Key components of this process,
such as the LD-anchor protein PLIN5 and carnitine
palmitoyltransferase 1, help mitigate lipid accumulation in LDs,
thus enhancing mitochondrial fatty acid oxidation (FAO) and the
risk of ferroptosis (82).
Through the PINK1/Parkin-mediated mitophagy pathway, damaged
mitochondrial-LD complexes are engulfed and degraded by lysosomes,
and the released FFAs further accelerate the ferroptosis process
(83). Additionally, the
PINK1/Parkin pathway promotes the ubiquitin-mediated degradation of
the mitochondrial iron transporters SLC25A37 and SLC25A28, which
enhances mitochondrial sensitivity to ferroptosis. Inhibition of
this pathway leads to disrupted mitochondrial iron-dependent immune
metabolic function (84).
Hypoxic microenvironments markedly diminish the
radiosensitivity of tumor cells and are a major factor contributing
to radiation resistance (85).
Hypoxia induces the expression of BCL2-interacting protein 3
(BNIP3), which integrates into and anchors to the OMM. By
competitively binding to the BH3 domain and activating the PI3K
pathway, BNIP3 promotes the initiation of mitophagy (86). Under hypoxic conditions, ROS
production increases, promoting the formation of PUFA-PLs through
the hypoxia inducible factors (HIFs)-hypoxia inducible lipid
droplet associated (HILPDA) axis. The LD-associated protein HILPDA
remodels the cellular lipidome, particularly altering the levels of
mitochondrial cardiolipin (CL). The HILPDA-CLS1 axis further
enhances the accumulation of CL, which promotes mitophagy induced
by IR (87). Therefore,
mitophagy-dependent ferroptosis may represent a key pathway for
enhancing radiosensitivity in hypoxic solid tumors. Furthermore, IR
activates multiple signaling pathways that regulate mitochondrial
metabolic reprogramming and ferroptosis. These pathways, including
AMPK/NF-κB, JAK2/STAT3 and PI3K/Akt/mTOR, activate the
reprogramming of mitochondrial glycolysis and lipid metabolism,
thereby enhancing ferroptosis susceptibility (3).
Mitochondrial activity-driven innate and adaptive
immune responses also serve a key role in the IR-mediated
enhancement of ferroptosis sensitivity in tumor cells (15). Upon IR exposure, the mitochondrial
metabolism of immune cells, such as T cells, monocytes, macrophages
and B cells, becomes increasingly reliant on FAO as a substrate.
This metabolic shift serves as a critical endogenous trigger for T
cell exhaustion (88). Elevation
of FAO leads to mitochondrial depolarization, impaired biosynthesis
and excessive ROS production, thereby inducing oxidative stress.
Furthermore, FAO inhibits the proteasomal degradation of HIF1α,
mediating the glycolytic reprogramming of precursor exhausted T
cells. This reprogramming drives their transcriptional and
metabolic transformation into terminally exhausted T cells
(89).
The newly identified metabolic reprogramming and
autophagy pathways offer valuable insights into how modulation of
mitochondrial function and ferroptosis mechanisms can enhance the
efficacy of clinical radiotherapy for radiation-resistant tumors.
These findings potentially provide novel therapeutic targets and
sensitization strategies for radioimmunotherapy (Fig. 2).
Mitochondrial dysfunction in various cell types,
including tumor cells and immune cells within the TME, serves a
pivotal role in tumor progression and immune evasion (90). Specifically, during T cell
activation, naïve T cells undergo a metabolic shift from OXPHOS and
FAO to aerobic glycolysis and fatty acid synthesis. During this
mitochondrial reprogramming, mitochondria accumulate beneath the
activated T cell receptor clusters, promoting mitochondrial fission
and concurrent relaxation of the inner membrane cristae. This
process stimulates mitochondrial activity, including increased
production of mtROS and ATP synthesis (91). This metabolic transition is
essential for T cell activation and supports their short-term
immune responses. However, as T cells differentiate into memory T
cells or Tregs, mitochondrial metabolism gradually shifts back to
OXPHOS and FAO to support cell survival, maintain cellular
phenotype and ensure immune tolerance or immunosuppressive
functions (76). In the TME,
tumor-infiltrating T cells exposed to chronic hypoxia environments
sustained mitochondrial dysfunction due to aberrant activation of
the Akt1-PGC1α signaling pathway, leading to persistent
mitochondrial damage. This metabolic dysfunction weakens T cell
anti-tumor immunity, inhibits cytokine secretion and ultimately
facilitates tumor immune evasion (92). Similarly, the immune response of
natural killer (NK) cells is significantly influenced by
mitochondrial metabolic alterations. During NK cell activation,
glycolytic capacity and basal OXPHOS rates increase remarkably.
However, in the transition to memory NK cells, damaged mitochondria
are removed via mitophagy-related proteins such as BNIP3(L),
thereby reducing mtROS production and supporting the formation of
memory NK cells (93). By
contrast, within a hypoxic TME, tumor-infiltrating NK cells exhibit
severe mitochondrial fragmentation, which impairs their
tumor-killing capacity and immune surveillance function, thus
promoting tumor immune evasion (94). Furthermore, mitochondrial
metabolic states profoundly impact macrophage polarization and
function within the TME. Upon M1 polarization, macrophages shift
their mitochondrial metabolism from OXPHOS to aerobic glycolysis,
accompanied by increased mitochondrial fission and elevated mtROS
production. By contrast, M2 polarization is characterized by
enhanced mitochondrial fusion, increased OXPHOS and FAO (95). These metabolic reprogramming
processes not only govern macrophage polarization but also directly
regulate their immune functions and responses to tumor progression.
Therefore, dynamic alterations in mitochondrial metabolic states
and morphology have a direct impact on immune cell polarization and
immune efficacy within the TME, serving a crucial role in tumor
immune evasion (Fig. 3).
IR-induced mitochondrial stress triggers the release
of mtDNA into the cytoplasm and extracellular space, where it
functions as a damage-associated molecular pattern (DAMP) that
activates pattern recognition receptors such as Toll-like receptors
(TLRs) and NOD-like receptors (NLRs). This activation sets off a
cascade of innate immune signaling (27). Notably, NLRP3 recognizes cytosolic
mtDNA, initiating caspase-1 activation, and promoting the cleavage
and maturation of the inflammatory cytokines IL-1 and IL-18. These
cytokines recruit T lymphocytes, macrophages and neutrophils,
thereby amplifying the immune response (96). In normal cells, caspase-dependent
mitophagy serves to mitigate immune signaling induced by mtDNA by
clearing damaged mitochondria. However, under pathological
conditions, impaired mitophagy or caspase-dependent mtDNA release
may convert immunologically silent cell death into ICD. In the
absence of caspases, MOMP activates the mtDNA-STING pathway,
initiating antitumor immune responses (97). IR also upregulates the expression
of mitochondrial fission protein 1 Drp1, contributing to
mitochondrial dysfunction and subsequent mtDNA release. This
extracellular mtDNA activates immune cells via the cGAS-STING and
TLR9-NF-κB pathways, modulating the polarization and function of
immune cells, including T lymphocytes, macrophages and DCs
(98). Thus, IR-induced ICD and
released mtDNA serves a dual role in tumor immune evasion and
activation. On one hand, mtDNA enhances the host's antitumor immune
response by stimulating immune reactions. On the other hand,
IR-induced ICD may also foster tumor immune evasion. Therefore, IR
not only activates immune responses through mtDNA release but also
modulates immune evasion via mitophagy regulation (99).
ROS serve a pivotal role in tumorigenesis,
particularly in the inflammatory TME, where they contribute to the
formation of immune-suppressive environments (100). Elevated ROS levels inhibit the
formation of TCR-antigen peptide-MHC complexes on the surface of
infiltrating T cells, thereby impairing T cell activation and
facilitating tumor immune escape (101). mtROS regulate immune cell
phenotypes and functions, thus supporting the establishment of an
immune-suppressive TME (102).
For instance, HIF-1α-induced mitochondrial Lon protease promotes
mtROS production through interaction with pyrroline-5-carboxylate
reductase (P5CRs), which in turn activates the NF-κB pathway,
leading to the secretion of immune-suppressive cytokines such as
IFN-γ and TGF-β by tumor cells (103). In addition, mtROS can further
enhance Lon protease expression, activate the mitochondrial
Na+/Ca2+ exchanger and regulate mitochondrial
calcium efflux, thus improving tumor cell resistance to cisplatin
(24). The central role of mtROS
in immune evasion underscores the importance of understanding the
complex regulatory mechanisms between mtROS and immune cell
activation in the TME. It is crucial for enhancing
radioimmunotherapy through mitochondrial ferroptosis sensitization.
Tumor-associated fibroblasts amplify oxidative stress in
surrounding monocytes, promoting their differentiation into MDSCs,
which in turn inhibit CD8+ T cell proliferation
(104). Elevated ROS levels,
through pathways involving HIF-1α and Lon protease, contribute to
the generation of immune-suppressive cells such as MDSCs,
tumor-associated macrophages (TAMs) and Tregs, thereby further
promoting immune suppression (105). ROS also alter the immunogenicity
of antigen peptides in antigen-presenting cells, affecting the
interaction between damage-associated molecular patterns (DAMPs)
and DC receptors, thus inhibiting antitumor immunity triggered by
ICD. Conversely, in the antitumor immune response, activated T
lymphocytes and NK cells utilize ROS to recruit neutrophils and
macrophages, thereby enhancing tumor cell killing. In reduced
GSH-deficient Tregs, abnormal serine metabolism leads to oxidative
stress, which downregulates Foxp3 expression and impairs the
immune-suppressive function of Tregs (106). Therefore, the levels and
sustained production of ROS in both tumor cells and immune cell
subsets are critical factors in determining the occurrence of ICD
and its capacity to induce effective antitumor immunity.
Macrophages are key immune cells within the TME,
serving a crucial role in maintaining immune homeostasis during
tumor progression. Tumor cells remodel the surrounding and distal
microenvironments by secreting tumor-derived factors that activate
monocytes and macrophages in circulation or local tissues, thereby
accelerating tumor progression (107,108). While mtROS were once regarded as
harmful byproducts of mitochondrial metabolism, recent research
underscores their signaling roles in preventing excessive immune
responses, particularly in regulating macrophage immune functions
(109). A previous study has
shown that mitochondrial Lon protease expression is elevated in
M2-type macrophages, suggesting that, during tumorigenesis,
macrophages regulate Lon expression through multiple signals to
induce mtROS generation, thereby serving a critical role in the
differentiation of TAMs (110).
Radiotherapy enhances antitumor immunity through
multiple mechanisms, notably inducing tumor ICD, which activates
adaptive anti-tumor immune responses. IR promotes the release of
double-stranded DNA (dsDNA) from the nucleus, leading to its
accumulation in tumor-derived exosomes and increasing OMM
permeability, thereby exposing mtDNA in the cytoplasm (111). As potent mediators, dsDNA and
mtDNA initiate the cGAS-STING pathway, upregulating IFN I
transcription, which activates the innate immune system, promotes
T-cell activation and suppresses tumor growth. Additionally, IR
induces the expression of MHC class I molecules and
tumor-associated antigens on tumor cell surfaces, while increasing
the exposure of calreticulin, HMGB1 and ATP, expanding the antigen
pool for presentation. This further enhances tumor immunogenicity
and promotes immune responses within the TME (112). Furthermore, IR stimulates the
release of inflammatory mediators and chemokines, such as CXCL9,
CXCL10 and CXCL11, from tumor and stromal cells. These factors
increase the infiltration of DCs, macrophages and T cells,
triggering both local and systemic antitumor immune responses
(113). These immune-enhancing
mechanisms suggest that radiotherapy not only exerts direct
cytotoxic effects on tumor cells but also significantly activates
the host immune system by reshaping the TME. When combined with
anti-PD-L1 immunotherapy, IR further reduces the accumulation of
MDSCs in the TME, creating a more inflammatory environment and
effectively reversing immunosuppression (114).
However, under certain dosing schedules and time
gradients, radiotherapy may also induce immunosuppressive effects
(115). These effects, driven by
alterations in the tumor hypoxic microenvironment, particularly
metabolic reprogramming and expansion of immune-suppressive cells
such as Tregs, may impair therapeutic efficacy and promote tumor
immune escape. IR can activate the GPR81/mTOR/HIF-1α/STAT3 pathway
by enhancing tumor cell glycolysis, which in turn promotes MDSC
activation in the TME (116).
Additionally, tumor metabolic reprogramming increases mitochondrial
FAO, providing ATP through mitochondrial catabolism, thus
facilitating tumor cell radioresistance. FAO upregulates CD47
transcription via the citrate-acetyl-CoA-RelA pathway, further
contributing to immunosuppression by protecting radioresistant
tumor cells from macrophage-mediated attack (116). The sustained activation of
HIF-1α by IR not only maintains the hypoxic microenvironment but
also drives macrophage subtypes (such as Macro-HK2, Macro-HSP and
Macro-MT) toward a pro-angiogenic phenotype. These macrophages
secrete additional chemokines, which recruit immunosuppressive
neutrophils after radiotherapy (117).
Under conventional fractionated radiotherapy,
sufficient radiotoxicity depletes circulating peripheral blood
monocytes and induces tumor cells to secrete Gal-1, which promotes
T-cell apoptosis (118). Tumor
cells subjected to repeated irradiation induce chronic expression
of FN I and IFN-γ, upregulating PD-L1 and IDO, leading to T-cell
exhaustion. This process is further enhanced by the IR-activated
cGAS-STING signaling pathway, which mobilizes Tregs and MDSCs while
inhibiting effector T-cell function (119). In local radiotherapy, IR
upregulates the secretion of CCL2 and CCL5, recruiting monocytes
and activating Tregs in a TNF-α-dependent manner, further
diminishing the therapeutic effect of radiotherapy (120). In later stages of radiotherapy,
the proportion of terminally exhausted CD8+ T cells increases,
along with upregulated exhaustion markers such as Pdcd1, Lag3 and
Tigit. This is accompanied by a limited maturation of DCs,
impairing their ability to activate CD4+/CD8+
T cells and exacerbating T-cell dysfunction (121).
Although radiotherapy combined with anti-PD-1
antibodies enhances tumor control via a CD8+
T-cell-dependent mechanism in certain therapeutic regimens,
low-dose fractionated radiotherapy (such as 2 Gy x10) may inhibit
IFN-γ expression in tumor-specific CD8+ T cells within
draining LNs. This effect is closely linked to radiation-induced
lymphopenia and the immunosuppressive TME (122). In localized radiotherapy,
selective lymph node irradiation (which is effective in addressing
subclinical lymph node micrometastases) may contribute to an
immunosuppressive TME when combined with anti-CTLA-4 antibodies.
This combination upregulates PD-L1 expression, leading to T-cell
exhaustion and radioresistance (123).
Among the immunomodulatory mechanisms of
radiotherapy, ferroptosis has emerged as a critical effector
pathway. Ferroptosis is not only a form of cell death but also a
potential mechanism through which radiotherapy induces ICD, thereby
activating antitumor immunity (124). IR induces ICD, prompting
activated CD8+ T cells in the TME to release IFN-γ. This
process inhibits system XC-(SLC3A2 and SLC7A11) expression, reduces
cysteine uptake by tumor cells and impairs the chelation of
GSH-cisplatin complexes, thus diminishing the ferroptotic defense
system and potentially reversing cisplatin-based chemoresistance
(125). Furthermore, IR remodels
the lipid profile of tumor cells, increasing the incorporation of
linoleic acid into C16- and C18-acyl PLs in an ACSL4-dependent
manner, thereby inducing ferroptosis (126). IFN-γ secreted by Th1, NK and NKT
cells can further promote ferroptosis by interacting with specific
fatty acids in the TME, thereby enhancing antitumor immunity
(127). This suggests a complex
interplay between ferroptosis, radiotherapy and immune responses,
presenting novel therapeutic targets for radioimmunotherapy
strategies. Within tumor cells, DNA damage sensors (including
ATRIP, Rad24p, γH2AX, NBS1, BRCA1/2, Ku70/80 and RNA polymerases)
recognize radiation-induced damage signals and recruit core DNA
damage response kinases ATM, ATR and DNA-dependent protein kinase
(DNA-PK) to DNA break sites, initiating repair mechanisms (128). Previous research has shown that
IR-activated ATM kinase, together with IFN-γ, synergistically
suppresses SLC7A11 expression and cysteine uptake, promoting lipid
peroxidation and ferroptosis, thus enhancing CD8+
T-cell-mediated antitumor immunity (129,130). This highlights the dual role of
ATM in radiation biology. Inhibition of ferroptosis diminishes the
efficacy of immune checkpoint inhibitors (ICIs) in combination with
radiotherapy, while inactivation of SLC7A11 enhances the
synergistic effects of ICIs and IR (131). Additionally, resistance to
ferroptosis mediated by lysosomal exocytosis pathways has been
negatively correlated with the efficacy of tumor
radioimmunotherapy. Although previous studies suggest that
tumor-derived CD8+ T cells exhibit elevated levels of
lipid peroxidation within the TME, thereby increasing their
susceptibility to ferroptosis (an important factor influencing
radiotherapy efficacy), the exact mechanism by which DC function
and antitumor immunity are influenced by radiotherapy-induced
ferroptosis warrants further investigation (132-134). Ferroptosis in immune cell
subsets can also modulate immune responses within the TME. Tumor
cells damaged by radiation typically exhibit dysregulated lipid
metabolism, while tumor-infiltrating T cells accumulate lipids in a
CD36 receptor-dependent manner, increasing intracellular oxidized
low-density lipoprotein levels, which induces lipid peroxidation
and ferroptosis. Inhibition of CD36 reduces ferroptosis in
CD8+ T cells, preserves antitumor immunity while
maintaining radiation-induced damage and enhances the efficacy of
immune checkpoint blockade (135). Activation of the ER stress
response factor X-box binding protein 1 (XBP1) in DCs inhibits T
cell-DC interactions by driving abnormal lipid accumulation.
Silencing XBP1 improves the antitumor and immune-stimulatory
functions of DCs, suggesting that targeting the ER stress response
could enhance antitumor immunity and promote ferroptosis in tumor
cells (136).
The role of granulocytes in ferroptosis within the
TME is still under extensive investigation. Granulocytes isolated
from mouse glioma models have been shown to transfer
myeloperoxidase to tumor cells via cytoplasmic vesicles, thereby
inducing lipid peroxidation products and triggering ferroptosis in
tumor cells (137). Granulocytic
myeloid-derived suppressor cells (G-MDSCs) in the TME are highly
sensitive to ferroptosis. They release oxidized lipids that
suppress T-cell activity, thereby contributing to immune evasion.
Beyond G-MDSCs, T-cell subsets may also undergo ferroptosis under
different environmental conditions (138,139). In Treg cells, the deletion of
GPX4 following TCR signaling leads to lipid peroxidation and
ferroptosis, which inhibits tumor growth and enhances antitumor
immunity (140). By contrast,
the deletion of GPX4 in CD8+ T cells results in the
failure of antigen-stimulated T-cell proliferation, attributed to
the rapid accumulation of membrane lipid peroxides and ferroptosis
within the cells. Furthermore, the suppression of GPX4 expression
in naïve CD4+ T cells prevents the generation of
follicular helper T (Tfh) cells and impedes germinal center
responses, limiting antibody production (141). Although T-cell proliferation
in vitro depends on system XC-, this transporter is not an
essential factor for T-cell proliferation or primary/memory immune
responses in vivo, with cysteine's role potentially
compensated by other mechanisms. Ferroptotic cells release
surface-exposed oxidized lipid species, such as SAPE-OOH, which
deliver key phagocytic signals, enhancing macrophage-mediated
phagocytosis via TLR2 (142).
However, the regulatory mechanisms of SAPE-OOH and the
immunogenicity of the TLR pathway remain incompletely understood.
Therefore, the composition of the TME serves a decisive role in
determining whether ferroptosis induces immune suppression or
activation. Before utilizing ferroptosis induction as a strategy to
sensitize radioimmunotherapy, targeted therapies for specific
immune cell populations may be required.
Inducing mitochondrial ferroptosis has emerged as a
promising approach to enhance tumor radiosensitivity in hypoxic
microenvironments (143).
IR-induced incomplete MOMP is a critical factor contributing to
radiation resistance. This process leads to the upregulation of
phosphorylayed-eIF2α and ATF4, which exacerbates tumor
radioresistance (144).
Liposomal formulations containing metformin and 2-deoxyglucose, by
targeting ATF4, effectively reverse radioresistance in CRC,
preventing T lymphocyte exhaustion and enhancing the efficacy of
fractionated radiotherapy through ferroptosis sensitization
(145). PGC1α, a key regulator
of mitochondrial metabolism, is recognized by DNA-PK under IR
conditions, promoting its ubiquitination and degradation. This
contributes to radioresistance in glioma subtypes. Therefore, the
use of the PGC1α activator ZLM005 can reactivate mitochondrial ROS
(mtROS) production and upregulate various forms of cell death,
including ferroptosis, thereby enhancing radiosensitivity (146). Additionally,
subcellular-targeted nanostructures, including DHODH inhibitors
such as QSSP, can enhance radiosensitivity by disrupting the
ferroptotic defense system. The mitochondria-targeted ferroptosis
inducer IR780-SPhF, which exhibits specific GSH-responsive
properties, induces mitochondrial redox imbalance, offering a novel
treatment strategy for breast cancer (147). Tubastatin A inhibits GPX4 enzyme
activity in a concentration- and time-dependent manner,
synergistically enhancing ferroptosis and sensitizing breast cancer
cells to radiotherapy (148).
Apart from targeting the ferroptosis defense system,
regulating the concentration of metal ions such as Fe2+
within mitochondria serves a key role in enhancing
ferroptosis-mediated radiosensitization (48). In nasopharyngeal carcinoma,
previous research has demonstrated that nanocarriers targeting
circular (circ) RNA circADARB1 can elevate intracellular iron ion
concentrations, thereby promoting radiotherapy-induced ferroptosis
and increasing radiosensitivity. Self-assembled pH-sensitive
superparamagnetic iron oxide nanoclusters enhance
mitochondrial-localized ferroptosis and apoptosis, synergistically
sensitizing tumors to radiotherapy (149). Cationic nanometal-organic
frameworks such as Th-Ir-DBB/digoxin, developed for ICD-induced
ferroptosis, utilize mitochondrial targeting and cholesterol
depletion to enhance the antitumor efficacy of
radiotherapy-radiodynamic therapy (150).
In the era of radioimmunotherapy, radiation
resistance and immune suppression within the TME often limit the
effectiveness of radiation-induced antitumor immune responses.
Ferroptosis has emerged as an effective strategy to enhance
antitumor immunity in this context (Fig. 4) (151). Targeting macrophage
membrane-coated biomimetic nanoparticles enables immune camouflage
to evade phagocytosis by the mononuclear phagocyte system, damaging
mitochondria and inducing ferroptosis in glioblastoma cells
(152). The
mitochondrial-targeting synthetic cluster Au25(S-TPP)18 inhibits
the thioredoxin reductase system, enhancing mtROS production. This
cluster exhibits potent radiosensitizing effects, induces a
bystander effect and activates the immune response (153). Tri-metallic nanoparticles
(AuBiCu-PEG NPs) with dual enzymatic activities not only promote
ICD induced by radiotherapy and enhance antitumor immunity, but
also effectively reverse radiation-induced PD-L1 upregulation.
These NPs suppress tumor immune evasion, reshape the immune
microenvironment and synergistically sensitize radiotherapy through
X-ray deposition, hypoxia alleviation and the induction of
ferroptosis and cuproptosis (154). Fe3O4-αPD-L1 nanoprobes, when
combined with radiotherapy, specifically target MDSCs, modulating
lipid and amino acid metabolism, particularly unsaturated fatty
acids and antioxidant metabolites associated with ferroptosis. This
approach reprograms the tumor immune-suppressive microenvironment,
promoting both local and systemic antitumor immune responses
(155). Equally important,
iron-containing hyaluronic acid (HA) NPs, which internalize by
high-affinity interactions with overexpressed CD44 receptors
through HA, generate lipid ROS. When combined with radiotherapy,
these nanoparticles induce both mitochondrial apoptosis and
ferroptosis (156).
Additionally, CSM nanoparticles loaded with single-atom
nanocatalysts (SAzyme), and manganese carbon monoxide enhance FLASH
radioimmunotherapy by inducing ferroptosis through multiple
pathways, including GSH depletion and CD8+ T-cell
infiltration (157). Other
ferroptosis-inducing NPs, such as BZAMH NPs, 8HSA8 NPs, Au/CuNDs
and Cu2WS4-PEG, also serve crucial roles in sensitization of
radioimmunotherapy (158).
Radiopharmaceutical therapy (RPT), or targeted
radionuclide therapy, directly treats malignant tumors by
delivering radioactive atoms (β- or α-particles) to the tumor site
(159). Compared with
X-ray-mediated IR, RPT allows for precise delivery of radiation to
cancer cells or the TME, maximizing tumor cell killing while
sparing surrounding healthy tissues (160). For instance, 3-nm
monocrystalline iron NPs (iRGD-bcc-USINP), when combined with a
PD-L1 blocking agent, target ferroptosis and synergistically exert
antitumor immune effects. However, ultra-small NPs (<6 nm)
demonstrate poor tumor accumulation (161). Particle size-optimized NPs,
assembled with radiopharmaceuticals such as USINP-131I-aPD-L1,
promote ROS production and enhance ferroptosis induced by USINP,
activating immune pathways and synergizing with PD-L1 blockade to
enhance antitumor immune responses. Furthermore, the 124I-P/C@
CMLvs system, combined with PET imaging tracer, can synergistically
enhance ferroptosis and necroptosis, inducing lung cancer
regression and improving the efficacy of anti-PD-L1 immunotherapy
(162).
In addition to enhancing radiotherapy, mitochondrial
ferroptosis can also sensitize emerging tumor treatments, such as
photothermal therapy (PTT), photodynamic therapy (PDT), and
sonodynamic therapy (SDT) (163). The IR780/Ce@ EGCG/APT
nanoreactor, by combining ferroptosis with PTT, improves the
immune-suppressive microenvironment in breast cancer and activates
systemic immune responses, leading to long-term immune memory.
Mitochondria-specific type I PDT mediated by organic NIR-II
photosensitizers (TPEQM-DMA) and two-photon nanosensitizers
(IR-g-C3N4) disrupt the lipid repair system, resulting in
mitochondrial dysfunction and induction of both apoptosis and
ferroptosis, providing an effective phototherapy strategy for
hypoxic tumors (164).
Furthermore, the mitochondria-specific organic-metal ultrasound
sensitizer IRCur-Pt enhances the synergistic effect of ferroptosis
and SDT, further activating immune pathways. Pancreatic
cancer-specific antibody NRP2-guided MOFs@ COF nanocarriers target
and disrupt mitochondrial and ER homeostasis, inducing
autophagy-dependent ferroptosis while sensitizing chemotherapy and
SDT (165). In summary, inducing
mitochondrial ferroptosis through the disruption of iron ion
homeostasis and peroxidation intervention has emerged as an
effective strategy to improve the radiosensitivity of malignant
tumors and enhance the efficacy of radioimmunotherapy.
The present review summarized the research
advancements in novel radioimmunotherapy strategies, focusing on
the transition from 'ferroptosis' to 'mitochondrial dysfunction'.
Ferroptosis, a form of RCD, has recently been implicated in tumor
resistance to radiotherapy. Inducing ferroptosis by modulating iron
metabolism and redox imbalance has emerged as a promising strategy
to enhance the efficacy of radiotherapy [Table SI (166-276)]. Concurrently, radiation-induced
mitochondrial dysfunction serves as a critical pathway for ICD in
tumor cells. Radiotherapy-ICIs has shown considerable therapeutic
benefits in clinical studies across various cancer types. These
studies underscore the complex interplay between ferroptosis and
mitochondrial dysfunction in tumor treatment responses,
highlighting the potential of combination strategies that integrate
radiotherapy, immunotherapy and ferroptosis modulation.
Although the potential of ferroptosis and
mitochondrial dysfunction in enhancing radioimmunotherapy is
becoming increasingly apparent, the research presently described
demonstrates several unresolved paradoxes in the regulation of
ferroptosis. Specifically, i) in hepatocytes, while mtROS-activated
PERK signaling promotes arsenite-induced ferroptosis by
downregulating Mfn-2 and impairing MAMs function, its cleaved
C-terminal fragment paradoxically exerts protective effects against
alcoholic hepatocyte ferroptosis (75); ii) the complex role of cGAS-STING
in either promoting cell death (via pyroptosis) (40) or supporting cell survival (by
suppressing ferroptosis) (41);
iii) the TME presents even more complex dichotomies: Although
hypoxia generally diminishes radiosensitivity, hypoxia-induced
BNIP3 protein can stimulate mitophagy and elevate ROS production,
mechanisms known to potentiate ferroptosis and consequently improve
radiation response (86); and iv)
radiation-enhanced FAO exhibits dual effects: While increasing
tumor cell vulnerability to ferroptosis, it simultaneously induces
T cell exhaustion, ultimately attenuating anti-tumor immunity and
compromising radioimmunotherapy efficacy (88).
The current research still faces other challenges.
First, the immunogenicity of ferroptosis in different contexts
remains unclear. Second, whether DAMPs are released during
ferroptosis, and how these DAMPs mediate immune responses within
the TME, require further investigation. Additionally, the
interactions between various cell death pathways and the
optimization of drugs that either promote or inhibit ferroptosis
are critical issues that need to be addressed. Resolving these
questions will help clarify the precise role of ferroptosis in the
TME and provide new insights for cancer treatment.
These challenges collectively indicate that the
current understanding remains incomplete regarding the molecular
mechanisms of ferroptosis are not fully understood, particularly in
terms of its heterogeneous effects across different tumor types and
subcellular organelles, which warrants further exploration
[Table SII (277-430)] such as the impact of TME factors
(oxidative stress, hypoxia and lipid metabolism) on ferroptosis
susceptibility and the precise mechanisms by which ferroptosis
synergizes with radioimmunotherapy, including the efficacy of
radioimmunotherapy combined with ferroptosis modulation may vary
significantly depending on the clinical context. Therefore,
accurately assessing patient responses and resistance mechanisms
remains a key area of research. Furthermore, while the combination
of ICIs and radiotherapy has shown promise, the interactions
between immune-related side effects and radiotherapy-induced
toxicity have not been thoroughly evaluated. Balancing therapeutic
efficacy with safety and optimizing treatment regimens remains a
major challenge in clinical applications.
Future research should focus on several pivotal
areas. First, a deeper exploration of the molecular mechanisms
underpinning ferroptosis and mitochondrial dysfunction,
particularly their roles within different TMEs, is essential. By
utilizing molecular targeting technologies, the development of
novel drugs or small molecule modulators that specifically induce
ferroptosis or restore mitochondrial function could offer new
strategies to enhance radiotherapy efficacy. Second, there is a
need for the advancement of immune monitoring techniques,
particularly those aimed at precisely assessing the association
between immune system responses and tumor cell death. This will
provide the foundation for personalized treatment strategies.
Furthermore, combining modern gene-editing technologies with
immunotherapeutic approaches to overcome the current resistance to
radiotherapy will be a major focus of future research.
In conclusion, the combination of radiotherapy and
immunotherapy holds significant promise in cancer treatment.
However, to achieve widespread clinical application, several
mechanistic and clinical challenges must be overcome. Future
research will deepen the current understanding of the interactions
between ferroptosis, mitochondrial dysfunction and immunotherapy.
Based on these insights, more precise and safer treatment regimens
will be developed, offering patients with cancer a broader range of
therapeutic options.
Not applicable.
TW, XZ and XY conceived the study and wrote the
manuscript. AZ, YF, KC, HT, ZT and PZ conducted literature
search/selection and data extraction. XH and LY revised and edited
the manuscript. All authors have read and approved the final
manuscript. Data authentication is not applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
The present work was supported by grants from the National
Natural Science Foundation of China (grant no. 82172804), the
Yishan Research Project of Jiangsu Cancer Hospital (grant no.
YSPY202407) and Clinical Research Foundation of collaborative
innovation center for cancer personalized medicine (grant no.
JZ21449020210616).
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