Despite ongoing improvements in approaches to cancer
detection and treatment, cancer continues to pose a major public
health burden worldwide. For advanced malignancies, comprehensive
treatment strategies commonly include surgical resection,
chemotherapy, radiotherapy (RT) and combinations of these
modalities. As a cornerstone of oncologic treatment (1), RT has historically been effective
for managing advanced tumors (2-4).
Approximately 50 to 60% of patients with cancer receive RT for
primary or metastatic lesions, either as a standalone modality or
in combination with surgery and chemotherapy (5,6).
RT encompasses a broad range of regimens that can be
classified by fractionation, including conventional,
hypofractionation and hyperfractionation, and by delivery
technique, including three-dimensional (3D) conformal radiotherapy,
intensity-modulated radiotherapy (IMRT) and stereotactic body
radiotherapy (SBRT). The use of stereotactic RT has expanded
rapidly because it can deliver ablative doses to the target with
high precision, while limiting exposure of adjacent normal tissues
(7,8). Ionizing radiation directly damages
biomolecules such as DNA and indirectly generates reactive oxygen
species (ROS) via water radiolysis, thereby triggering oxidative
stress (9-11). This process results in DNA
lesions, such as double-strand breaks, and induces multiple forms
of cell death, including apoptosis, autophagy and necrosis,
ultimately eliminating cancer cells (12). The selection of definitive or
adjuvant RT depends on factors including tumor radiosensitivity.
Indications have broadened with high-precision fractionated
techniques such as stereotactic RT. For example, current guidelines
recommend stereotactic approaches in selected hepatocellular
carcinoma and in oligometastatic disease (8). However, RT efficacy is constrained
by multiple factors, among which the tumor microenvironment (TME)
is a key determinant.
The TME refers to the complex ecosystem surrounding
malignant cells, including immune cells, blood vessels,
extracellular matrix components and soluble mediators such as
cytokines. These components influence tumor evolution and treatment
responsiveness, creating a permissive niche that supports cancer
cell survival and proliferation (13,14). Cytokines are key mediators
through which immune cells coordinate immune responses, and major
classes include interleukins, interferons, members of the TNF
superfamily, chemokines and growth factors (15-19). More than 100 cytokines have been
identified, and their signaling cascades and biological functions
have been characterized in detail (16,20-26). Cytokines act through autocrine,
paracrine and endocrine modes and influence diverse cell
populations in the TME, thereby shaping clinical outcomes in cancer
(27). Accumulating evidence
supports the therapeutic value of cytokine administration and of
agents that block cytokine signaling. For instance,
granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes
antitumor immunity via dendritic cell activation and has been used
in approaches including GM-CSF gene-transduced tumor cell vaccines
(28-31), sipuleucel-T (32) and the oncolytic virotherapy
Talimogene laherparepvec (33).
In addition, neutralizing antibodies and small molecule inhibitors
directed against cytokines or their receptors have demonstrated
activity in cancer and in immune-mediated diseases (34). Recent translational studies have
increasingly focused on integrating RT with cytokine-directed
interventions. For example, the colony stimulating factor 1
receptor (CSF1R) inhibitor PLX3397 combined with RT antagonizes
CSF1R signaling and can deplete irradiation-recruited M2-type
tumor-associated macrophages (TAMs), thereby mitigating
RT-associated immunosuppression (35-37). Conversely, RT combined with G-CSF
or GM-CSF can enhance neutrophil-mediated antitumor functions by
increasing ROS generation and promoting cytotoxic T-cell
activation, which can improve local tumor control and induce
abscopal responses (38). In
addition, a mitochondria-targeted radionuclide,
223Ra-TPP, has been engineered to trigger mitochondrial
DNA damage and engage the cyclic GMP-AMP synthase (cGAS)/stimulator
of interferon genes (STING)/IL-1β axis, thereby amplifying systemic
immunity (39). These findings
indicate that defining key cytokine networks within the TME is
important for the rational design of immunotherapy strategies.
Tumor cells evade immune surveillance by
establishing an immunosuppressive microenvironment, a hallmark of
cancer. This state is maintained by immunosuppressive cells such as
TAMs and regulatory T (Treg) cells together with specific cytokines
(40,41). RT exerts complex and frequently
bidirectional effects on the TME. On the one hand, RT can stimulate
antitumor immunity and can function as an in situ
vaccination approach. Irradiation triggers immune-activating
events, including damage-associated molecular pattern release,
pro-inflammatory cytokine production and engagement of the
cGAS/STING axis (42).
Radiation-induced immunogenic cell death recruits immune cells and
promotes dendritic cell antigen presentation through
damage-associated molecular patterns and activation of the
cGAS-STING pathway and pattern recognition receptors, ultimately
activating CD8+ T cells. Higher intratumoral
CD8+ T-cell density is associated with favorable
outcomes after RT (40,43-48). RT can also reprogram neutrophils
toward an antitumor phenotype. These RT-activated neutrophils
produce increased ROS, directly kill tumor cells and secrete
pro-inflammatory factors such as TNF-α and interferon (IFN)-γ to
promote systemic immunity (38).
Administration of G-CSF further increases the number of RT-induced
antitumor neutrophils and enhances ROS production, accompanied by
upregulation of the antitumor N1 marker ICAM-1 (38,49). On the other hand, RT can induce
immunosuppression. For example, irradiation-induced increases in
ROS and hypoxia-inducible factor (HIF)-1α can promote the release
of TGF-β and C-X-C motif chemokine ligand (CXCL)12, driving the
expansion of Treg cells, myeloid-derived suppressor cells (MDSCs)
and cancer-associated fibroblasts (CAFs), enhancing M2 polarization
and increasing immunosuppressive cytokine production. In parallel,
immune checkpoint pathways, including programmed cell death 1
(PD-1) and cytotoxic T-lymphocyte associated protein (CTLA)-4 can
be upregulated, further constraining antitumor immune responses
(50-53). RT can also promote tumor cell
secretion of M-CSF via the NF-κB-p65 pathway, inducing TAM
polarization toward an M2 phenotype and increasing secretion of
IL-10 and Arginase 1 (54).
Furthermore, irradiated tumor cells may release exosomes enriched
in microRNA (miR)-21 that are transferred to TAMs via the CCL2 and
CCL3 axis, contributing to an immunosuppressive milieu (35). This remodeling may partially
explain why, in locally advanced non-small cell lung cancer, adding
programmed cell death ligand (PD-L1) blockade to standard chemoRT
improves outcomes, while >50% of patients later develop
progressive disease (55).
Traditional RT research has largely focused on
direct cytotoxic effects, with less emphasis on how RT regulates
the tumor immune microenvironment and systemic immunity. Beyond
inducing lethal DNA damage, RT promotes intercellular communication
by generating mediators such as ROS. ROS can function as
ligand-like cues that activate cell-surface receptors, thereby
initiating apoptosis or senescence in a stress-dependent manner
(56), promoting proliferation
(12,57), and orchestrating immune signaling
through the induction of pro-inflammatory cytokines, including IL-1
and TNF (40). Numerous
preclinical studies have established that host immune competence is
a key determinant of RT efficacy (58-60). These observations support a
conceptual shift in which RT is viewed not only as a cytotoxic
modality but also as a driver of cytokine network remodeling within
the TME. Ionizing radiation can influence therapeutic success by
initiating immune signaling cascades, positioning RT as a core
component of radioimmunotherapy (61).
Different RT modalities can regulate cytokine
programs in distinct ways. For example, ultra-high dose-rate Fast
Linear Accelerator-based Scanning Hybrid (FLASH) RT reduces the
release of profibrotic factors such as TGF-β and IL-1β, thereby
alleviating radiation-induced lung injury, while promoting
CD4+ T-helper-cell secretion of tissue-reparative
cytokines, including IL-10 and IL-22 (62,63). By contrast, proton therapy
leverages the Bragg peak to better spare circulating lymphocytes
and, when combined with immunotherapy, increases the frequency of
intratumoral IFN-γ-positive T cells, while suppressing TGF-β
signaling (64). These advances
provide a rationale for RT selection and customization in
immunotherapy-compatible treatment designs.
Building on this background, the present study
proposes a multi-layered framework integrating five dimensions: RT
parameters, key signaling axes, effector cells, organ-specific
contexts and clinical translation. First, the dynamic roles of
major cytokine families in the post-irradiation tumor immune
microenvironment were summarized, including IFN-I/III, chemokines
and key mediators, such as IL-1, IL-6, IL-10 and TGF-β. The focus
is on antagonistic and cooperative networks that balance immune
activation and immunosuppression. Second, focusing on macrophages
as a key effector cell population, their hub function in RT
responses through CSF1R and CCR2 signaling and downstream metabolic
reprogramming were examined, and mechanisms of polarization control
and paracrine circuits were summarized. Third, the analysis was
extended to organ-specific radiation injury by summarizing
tissue-characteristic cytokine signatures and candidate
interventional targets. Glial-cell activation mediated by IL-1β,
IL-6 and TNF-α in radiation-induced brain injury (RBI) was
analyzed. The review then delineated the development of pulmonary
radiation fibrosis dominated by TGF-β and IL-13. Mucosal barrier
dysfunction linked to IL-33 and TSLP in gastrointestinal injury was
then discussed. Subsequently, the roles of IL-1 and TNF in the
inflammatory cascade of oral mucositis were summarized. The
coupling between IL-6/STAT3 axis-driven regenerative repair and
TGF-β-mediated fibrosis in liver injury was also described.
Finally, from a translational perspective, key parameters in
combined RT and immunotherapy strategies were evaluated, including
fractionation selection, immunotherapy sequencing, candidate
synergistic dose windows and predictive biomarkers. This synthesis
is intended to support individualized evidence-based integration of
RT with immunotherapy (Fig.
1).
IFN-I represents the largest IFN family and includes
IFN-α, IFN-β, IFN-ε and IFN-ω, which signal through the type I IFN
receptor (IFNAR) (65). Burnette
et al (66) showed that
RT-mediated tumor control is lost in IFNAR-deficient mice,
indicating that host IFN-I signaling is required for RT-induced
antitumor immunity. The magnitude and duration of IFN-I signaling
can influence RT efficacy (66,67). IFN-I pathways can therefore exert
both promotive and inhibitory effects on RT responses through
immune mechanisms.
Augmenting local IFN-I signaling in the TME can
counteract immunosuppression and promote antitumor immunity.
Irradiation can induce tumor-infiltrating myeloid cells to produce
IFN-α and IFN-β through autocrine signaling. These IFN-I signals
propagate within the hematopoietic compartment and enable
tumor-infiltrating dendritic cells to cross-prime CD8+ T
cells, supporting adaptive immune attack on the tumor (66). This response is coupled to a
cytosolic DNA sensing cascade involving cGAS, STING and IFN
regulatory factor 3 (IRF3) (67). In this cascade, cGAS functions as
a cytosolic DNA sensor that allows dendritic cells to detect DNA
derived from irradiated tumors and represents a key node through
which RT initiates antitumor immunity (68). Ionizing radiation also induces
DNA strand breaks and micronuclei formation, and micronuclear DNA
can activate STING and TANK-binding kinase 1 (TBK1), thereby
stimulating IFN production (69,70). The resulting IFN release promotes
dendritic cell maturation and major histocompatibility complex
class I (MHC-I) upregulation, enhances tumor antigen
cross-presentation and elicits antigen-specific cytotoxic
T-lymphocyte responses that mediate antitumor efficacy (66,71,72).
Poly (ADP-ribose) polymerase (PARP) inhibition can
lead to cytosolic double stranded DNA accumulation, engage the
cGAS/STING/TBK1/IRF3 axis and induce IFN-I production and
associated immune programs (67,73). In triple-negative breast cancer
models, olaparib activates cGAS-STING signaling and drives mediator
release that activates dendritic cells, resulting in increased
CD8+ T-cell infiltration and activation (74). These findings suggest that PARP
inhibitors can cooperate with RT to engage innate and adaptive
immunity through a double-stranded DNA-driven cGAS/STING/IRF3/IFN-I
signaling pathway. Activation of the cGAS-STING pathway is often
accompanied by PD-L1 upregulation, which has been linked to IFN-I
activity (75,76). Accordingly, STING agonists have
been proposed as candidate sensitizers to PD-1 or PD-L1 checkpoint
blockade (77). Beyond IRF3,
STING can also engage IκB kinase and NF-κB-inducing kinase to
activate NF-κB, supporting antitumor effects across tumor
initiation, progression and metastasis (77-80).
IFN-I signaling is also constrained by negative
feedback circuits. Irradiation-induced STING and IFN-I signaling in
dendritic cells can activate STAT2 and increase expression of the
m6A reader YTH domain-containing family protein 1 (YTHDF1). YTHDF1
promotes translation of cathepsin A and cathepsin B mRNAs,
increases lysosomal protease abundance and accelerates lysosomal
STING degradation, thereby reducing IFN-I production and limiting
dendritic cell antitumor activity (81). In addition, neoadjuvant RT
studies in rectal cancer have identified an inflammatory CAF subset
characterized by high IRF1 expression. This subset is polarized by
IFN-γ signaling and recruits T cells and dendritic cells through
secretion of CCL4 and CCL5, thereby augmenting antitumor immunity
(82).
By contrast, intratumoral IFN-I activation has been
associated with unfavorable outcomes and resistance to several
treatment modalities including RT (83-86). In settings combining RT with
CTLA-4 or PD-L1 checkpoint blockade, IFN signaling can contribute
to treatment resistance (87).
Chen et al (88) reported
that genetic ablation of Ifnar1 enhances CD8+ T
cell-dependent antitumor responses after RT, and they identified
serine protease inhibitor b9 as a critical factor that is reduced
in Ifnar1-deficient tumor cells.
CC chemokines comprise a chemokine subfamily defined
by an N-terminal C-C motif (89). CCL2, also known as monocyte
chemoattractant protein 1 (MCP-1), can bind multiple receptors, and
RT can induce CCL2 expression (90,91). Within radiation-induced immune
responses, CCL2 exerts pleiotropic effects. It can act downstream
of IL-6 to mediate macrophage infiltration into tumors after
irradiation (92). RT can
activate STING signaling and increase IFN-I production, which can
induce CCL2, CCL7 and CCL12 expression and drive monocyte
trafficking into tumors (93).
In murine head and neck squamous cell carcinoma, a 7.5-Gy dose
increased CCL2 and promoted infiltration of TNFα-producing
monocytes and CCR2+ Treg cells. Monocyte-derived TNFα
activated Treg cells and could undermine RT responses (94). Tumor-derived CCL2 has also been
implicated in adaptive radioresistance in pancreatic ductal
adenocarcinoma models, in which CCL2 blockade improved the efficacy
of RT (95). Upregulation of
CCL2 has been linked to radiation toxicities, including
radiation-induced lung injury, radiation-induced liver injury and
cognitive impairment after RBI (96-98). CCL3, also known as macrophage
inflammatory protein 1α, contributes to RT responses. Through CCR1
engagement, CCL3 promotes type 2 T-helper (Th2)-cell infiltration
and exacerbates radiation-associated lung injury and fibrotic
remodeling. In hepatocellular carcinoma, combining CCL3 with RT
enhanced CD8+ T cell-driven antitumor immunity, and CCL3
has also been evaluated as a candidate predictor of breast cancer
RT response (99). CCL5, also
known as regulated on activation, normal T cell expressed and
secreted, can exert context-dependent effects. RT induces tumor
cells and mesenchymal stromal cells to release CCL5, which recruits
macrophages and can promote M2 polarization and metastatic
progression (100,101). By contrast, CCL5 can also
recruit CD8+ T cells and enhance antitumor immunity,
indicating that its net effect depends on tumor context and
radiation dose (102). CCL8,
also known as MCP2, binds multiple receptors, including CCR1, CCR2,
CCR3 and CCR5, and mainly recruits monocytes and Treg cells.
Thoracic irradiation elevates CCL8, enhances macrophage
infiltration and has been associated with increased pulmonary
metastasis in a preclinical study (103). CCL11, also known as eotaxin 1,
recruits eosinophils through CCR3. Radiation-associated increases
in CCL11 have been linked to injury across multiple tissues. In
intestinal radiation fibrosis, irradiation drives mucosal
myofibroblasts to secrete CCL11, which recruits eosinophils and
accelerates fibrotic progression (104). After radiation injury to skin
and brain tissue, increased CCL11 can also promote migration of
eosinophils and other immune cells to damaged sites, aggravating
inflammation and tissue injury (105,106). CCL7 has been implicated in
radiation-induced lung fibrosis. In a radiation-sensitive murine
model, CCL7 was found to be markedly induced and was able to
promote lung fibrosis by recruiting profibrotic immune populations
(107). CCL22 is constitutively
secreted by specific dendritic cell subsets in secondary lymphoid
organs, particularly the CD103+ CD11b−
CD8+ subset. By binding CCR4 on Treg cells, CCL22
promotes direct dendritic cell- and Treg-cell contact that
suppresses effector T-cell activation and proliferation. Loss of
CCL22 enhances vaccine-induced antigen-specific CD8+
T-cell responses and antitumor immunity (108).
Overall, CC chemokines function as regulators of the
RT-conditioned TME by coordinating monocyte influx, macrophage
polarization, trafficking of T cells and Treg cells, and
eosinophil-associated remodeling. Table I summarizes their reported net
effects on antitumor immunity, radioresistance and RT-associated
toxicity. Conversely, pro-immunogenic chemokines such as XCL1 and
CXCL16 can recruit cross-presenting dendritic cells and effector
CD8+ T cells to strengthen antitumor immunity (109,110), whereas axes such as
CXCL12/CXCR4 and CXCL8/CXCR1/2 promote vasculogenesis, DNA damage
repair and survival signaling that support recurrence and
radioresistance (111-113). More broadly,
radiation-responsive chemokine programs are emerging as important
determinants of immune-cell trafficking and treatment outcome; a
recent review summarized the central role of CC chemokines in
radiation responses, and experimental evidence in lung cancer
further showed that RT can enhance activation of CD8+ T
cells with high CXCR3 expression by inducing IFN-γ-mediated CXCL10
and ICAM-1 expression (114,115).
RT kills tumor cells by inducing DNA double-strand
breaks and simultaneously triggers dynamic changes in
pro-inflammatory and anti-inflammatory cytokine networks (Fig. 3). These changes can have opposing
consequences. Pro-inflammatory cytokines, including TNF-α, IL-6 and
IL-1β, can activate NF-κB, STAT3 and angiogenesis-related pathways,
thereby promoting tumor-cell proliferation and invasion and
contributing to radioresistance. For example, TNF-α overexpression
in non-small cell lung cancer is associated with reduced
radiosensitivity, and increased serum IL-1β, IL-6 and TNF-α in head
and neck squamous cell carcinoma is associated with worse outcomes
(116,117). RT-induced immune reprogramming
can also involve IL-6-dependent regulation. In nasopharyngeal
carcinoma, irradiation increases mTOR complex 1 activity and alters
p62 phosphorylation, which suppresses p62-dependent selective
autophagy and ultimately increases endothelial protein C receptor
(PROCR) expression. By promoting IL-6 secretion, PROCR suppresses
Th1 differentiation and compromises CD8+ T-cell effector
function, thereby attenuating antitumor immunity (118). IL-34 suppresses IL-12 in
post-irradiation TAMs, limiting recruitment and activation of
IFN-γ-producing CD8+ T cells and blunting RT-induced
antitumor immunity. In IL-34-deficient tumors, RT promotes
pro-inflammatory macrophage differentiation and IL-12 induction,
strengthening immune-mediated tumor eradication (119). Cytokines are also key mediators
of immunogenic cell death. Under immunogenic conditions, they can
drive dendritic cell maturation and antigen cross-presentation and
enhance CD8+ T-cell responses through NF-κB and IFN-I
pathways, contributing to abscopal effects. In breast cancer
models, combining irradiation with valproic acid reprograms the
irradiated field TME, increases CD8+ T-cell infiltration
and M1-like polarization and suppresses growth of distant lesions
(120,121). Anti-inflammatory mediators such
as IL-10 can mitigate normal tissue toxicity. For example,
low-level laser therapy can ameliorate oral mucositis in part by
reducing IL-6 (122). However,
excessive anti-inflammatory signaling can suppress immune
surveillance and is associated with reduced survival. For example,
in glioblastoma, dexamethasone-induced anti-inflammatory cascades
correlate with shorter survival (123). In specific contexts, such as
combination with γ irradiation, IL-10 upregulation has also been
reported to promote tumor-cell apoptosis, as observed with ebselen
combination therapy in breast cancer models (124). Radiation dose is a determinant
of the immune microenvironment. Low- and intermediate-dose RT tends
to favor M2-macrophage polarization and an immunosuppressive
microenvironment (125),
whereas high-dose RT combined with PD-L1 blockade can activate the
cGAS-STING pathway, amplify pro-inflammatory cytokine release and
enhance CD8+ T-cell responses, thereby increasing
abscopal effects (126). When
pro- and anti-inflammatory signals are imbalanced, TGF-β-driven
pathways may promote radiation fibrosis or radioresistance
(127), and excessive
anti-inflammatory signaling may weaken immune clearance and
increase the risk of recurrence (121). Clinically, modulation of
cytokine networks has been explored to remodel the TME. For
example, URB937-mediated suppression of IL-1β, IL-6 and TNF-α
mitigates radiation-induced lung injury (128), siltuximab improves RT responses
in multiple myeloma (129) and
CTLA-4 blockade can potentiate RT-induced abscopal effects
(130). To maximize antitumor
efficacy while minimizing adverse effects, real-time monitoring and
rational modulation of this network remain important (131).
Macrophages are key immune components of the TME and
contribute to tumor initiation, immune evasion and antitumor
immunity (Fig. 4) (132). RT can reshape the TME by
altering the polarization of TAMs (133). Different radiation doses can
promote transitions toward a pro-inflammatory M1 phenotype or an
anti-inflammatory M2 phenotype through NF-κB and downstream
cytokine signaling, resulting in dose-dependent immunomodulation
(125,134-137). Low-dose RT (<2 Gy) can
inhibit NF-κB p65 activity, reduce expression of pro-inflammatory
factors such as TNF-α and IL-1β, and increase TGF-β release,
thereby promoting an immunosuppressive M2 phenotype (125,134). Moderate-dose RT from 2 to 10 Gy
can activate NF-κB p65 p50 heterodimers, increase the secretion of
TNF-α, IL-6 and IL-12, upregulate M1 markers including CD80, CD86
and MHC-II, and suppress M2 markers such as CD163 and IL-10,
thereby enhancing antitumor immune responses (135,136,138). By contrast, high-dose RT >10
Gy can increase the expression of chemokines such as CCL2, CCL5 and
CXCL12 through hypoxia-induced HIF-1α signaling, driving monocyte
differentiation toward M2-like TAMs. High-dose RT can also favor
NF-κB p50 homodimer activity, upregulate immunosuppressive factors
including IL-10 and TGF-β, and contribute to tumor immune escape
(111,139,140).
TAMs modulate tumor radiosensitivity by secreting
cytokines and chemokines. CCL2 and CXCL6 secreted by M2-like TAMs
can recruit MDSCs or activate EMT programs, thereby promoting
radioresistance (93,141-143). After irradiation, tumor-derived
exosomes can transfer miR-193b-3p and hsa_circ_0001610 to TAMs and
reduce radiosensitivity through MAPK kinase kinase 3 repression or
PD-L1 upregulation (144,145). High-dose RT can also induce
CAFs to secrete CCL2, which cooperates with TAM-derived VEGF and
heparin-binding EGF-like growth factor to promote angiogenesis and
DNA damage repair, thereby enhancing radioresistance (146-148). Conversely, M1-like TAMs secrete
TNF-α and IL-12, promote cytotoxic T-lymphocyte recruitment and
enhance antigen presentation, which can counteract
immunosuppression and improve radiosensitivity (149,150). In addition, RT-derived
microparticles can activate the JAK/STAT pathway, promote
polarization toward M1 macrophages and induce the release of danger
signals such as ATP and high mobility group box 1 (HMGB1), thereby
enhancing immunogenic cell death (151,152).
Given the role of TAMs in radiosensitivity,
targeting macrophage-associated cytokines has become an important
strategy to improve RT efficacy. Inhibition of CCL2/CCR2 or
CCL5/CCR5 signaling can limit macrophage infiltration and M2
polarization (153). Anti-CSF1R
antibodies can block monocyte to macrophage differentiation, and
combining these agents with RT can delay tumor recurrence (37,154). VEGF-neutralizing antibodies can
counteract macrophage-driven angiogenesis (147,155). Nanotechnology-based delivery
approaches, such as nanogels carrying Toll-like receptor (TLR)7 or
TLR8 agonists, can reprogram macrophages toward an M1 phenotype
(156-159). Iron oxide nanoparticles can act
as radiosensitizers by increasing ROS and promoting the secretion
of pro-inflammatory cytokines such as IL-1β (151,160). In addition, RT-derived
microparticles co-expressing tethered (t)IL-15 and tCCL19 combined
with PD-1 inhibitors can activate CD8+ T-cells and
cooperate with macrophages to enhance antitumor activity (161).
In summary, RT regulates TAM polarization through
cytokine networks, particularly NF-κB, CCL/CCR and CSF1R signaling,
which represent central determinants of tumor radiosensitivity.
Although cytokine-targeted approaches and nanotechnology-based
delivery strategies have shown efficacy in preclinical studies,
heterogeneity in dose effects, potential normal tissue toxicity and
immune feedback resistance mechanisms such as compensatory PD-L1
upregulation remain key challenges for clinical translation
(162). Future studies using
single-cell analyses and related technologies are needed to define
functional heterogeneity among macrophage subsets and to support
individualized strategies for combining RT with immunotherapy.
RBI is a common adverse effect of tumor RT and
effective treatments remain limited (163,164). Cellular senescence is
considered a major risk factor for RBI initiation and progression
(165-167). RT can induce pericyte
senescence and promote the secretion of senescence-associated
secretory phenotype factors, including IL-6, TNF-α, IL-1β and CCL2,
which can disrupt blood-brain barrier (BBB) integrity and impair
endothelial tight junctions in vitro (168). These factors can further impair
endothelial, vascular, glial and hippocampal neuronal function
through paracrine signaling (169-172). Radiation injury can also cause
autophagy defects and lysosomal dysfunction in perivascular cells,
leading to the accumulation of toxic proteins, accelerated
senescence and demyelination of microglia, neurons and
oligodendrocyte progenitor cells, thereby worsening cognitive
dysfunction (173). Based on
these mechanisms, activation of autophagy or elimination of
senescent cells has been explored as a strategy to mitigate RBI.
For example, rapamycin enhances lysosome-mediated protein
clearance, suppresses perivascular cell senescence and partially
restores proliferative capacity (174,175). Dasatinib plus quercetin and
all-trans retinoic acid can selectively eliminate senescent
pericytes and reduce senescence-associated secretory phenotype
secretion, thereby improving BBB integrity and cognitive function
(176-178). In models driven by microglial
inflammation and neuronal loss, pregabalin has shown
neuroprotective effects by blocking HMGB1-mediated TLR2, TLR4 and
RAGE/NF-κB signaling and by reducing the production of IL-6, IL-1β
and TNF-α (179).
In RT for high-grade brain tumors and metastases,
neuron-derived ectodysplasin A2 receptor (EDA2R) has been proposed
as a predictor of early responses, such as neurocognitive
impairment after cranial irradiation, although the mechanism
remains elusive (180). In
cachexia-associated muscle atrophy, oncostatin M upregulates EDA2R
expression through activation of the noncanonical NF-κB pathway
(181). Another report
suggested that after hypoxic injury, EDA2R can modulate
inflammatory mediators, including TNF-α and IL-1β (182). Based on these observations, a
plausible mechanism is that RT acutely activates multiple
immune-cell types, including microglia (183,184), and increases the secretion of
inflammatory mediators after the peak dose. Under these conditions,
oncostatin M may promote EDA2R upregulation through NF-κB signaling
and thereby modulate the local inflammatory microenvironment
(Fig. 5) (169,170,185,186). In addition, upregulation of
CCL8 in the hippocampus can mediate macrophage accumulation and
exacerbate neuroinflammation, contributing to cognitive impairment
after cranial irradiation (112).
Radiation-induced lung injury arises from direct
irradiation-mediated cytotoxicity in normal lung tissue and the
subsequent inflammatory and fibrotic responses (Fig. 6) (187). Sustained post-irradiation
increases in cytokines such as IL-6 can damage type I alveolar
epithelial cells (AECI) and stimulate proliferation of AECII
(188). Subsequently, at ~6 to
8 weeks after irradiation, a second wave of cytokines including
TNF-α can contribute to acute pneumonitis (189). Ionizing radiation damages
alveolar epithelial cells and vascular endothelial cells, releasing
damage-associated molecular patterns (DAMPs) and cytokines
including TNF-α, IL-1β, IL-6, IL-8 and TGF-β1. These mediators
activate the NF-κB and MAPK pathways, promote the recruitment of
macrophages, neutrophils and dendritic cells, and amplify local
inflammation (190-192). In parallel, injured AECII show
reduced surfactant production, impaired tissue homeostasis and
activation of EMT via TGF-β1 and β-catenin signaling, promoting
fibrotic progression (193).
Radiation can also polarize lung resident macrophages toward an M1
phenotype, leading to the production of ROS and chemokines such as
CCL2, CXCL9 and CXCL10. This process promotes continued
CD8+ T-cell infiltration and exacerbates tissue injury
(133,194). In the late phase,
radiation-activated cGAS/STING signaling can promote macrophage
polarization toward an M2 phenotype through the regulation of CCL2
and can increase the secretion of profibrotic factors such as TGF-β
and platelet-derived growth factor (PDGF). These changes induce
fibroblast to myofibroblast differentiation, increase extracellular
matrix deposition and contribute to radiation-induced pulmonary
fibrosis (195-197). Macrophage-derived CCL22 is
selectively upregulated in rat models of radiation pneumonitis
(198). Targeting mediators
such as TGF-β, alone or in combination, and strategies that target
CCL22 through the TNF-related apoptosis-inducing ligand pathway
have been proposed for severe radiation lung toxicity (199). A previous study also indicated
that irradiation-activated bronchial club cells can modulate the
local immune microenvironment by secreting club cell secretory
protein, suppressing MDSCs and enhancing T-cell function,
suggesting that distinct pulmonary cell types contribute to
immunoregulation in lung injury and fibrosis (200). In addition, chemokines
including CCL5, CCL8 and CCL3 have been linked to the progression
of radiation-induced lung injury.
To reduce the risk of radiation-induced lung injury,
clinical management should integrate advanced planning and delivery
techniques such as IMRT and SBRT with evidence-based supportive
measures, including anti-inflammatory agents, immunomodulatory
strategies, and, in selected contexts, mesenchymal stromal
cell-based interventions, to control radiation-induced inflammation
and limit fibrotic progression. In parallel, the development of
therapeutics that target key cytokine pathways implicated in
pneumonitis and fibrosis remains an important research direction
for the prevention and treatment of radiation-induced lung
injury.
Radiation-induced gastrointestinal injury is a
common complication of cancer RT. Radiation esophagitis is a major
dose-limiting toxicity in RT for lung cancer and head and neck
squamous cell carcinoma (Fig.
7). Among patients with non-small cell lung cancer receiving
concurrent chemoRT, the incidence can reach 95 and 33% experience
grade 3 or higher events. Similar rates have been reported for 3D
conformal RT, IMRT and proton beam therapy (201-203). Evidence suggests that IFN-α
acts as a pro-inflammatory mediator in radiation esophagitis
(204). Plasmacytoid dendritic
cells (pDCs) in the esophageal mucosa can recognize endogenous RNA
and DNA released as damage-associated molecular patterns released
after tissue injury via TLR7 and TLR9, producing large amounts of
IFN-α and serving as a major source of IFN-I in radiation
esophagitis (205-207). Depletion of pDCs using
anti-CD317 antibodies or inhibition of pDCs function with
bortezomib can suppress IFN-α upregulation and alleviate mucosal
inflammation and tissue injury. These findings support a
pro-inflammatory plasmacytoid dendritic cell IFN-α pathway and
provide a rationale for targeted intervention. Beyond IFN-α,
upregulation of IL-16, CCL3 and CCL7 is associated with increased
esophagitis severity. By contrast, upregulation of CCL5, CXCL12,
CCL22 and IGF-1 is consistent with trends toward injury repair
(108).
Radiation-induced rectal injury refers to rectal
damage caused by RT for pelvic malignancies and is commonly
categorized as acute or chronic, with 3 months used as a practical
cutoff (208). Preclinical
studies indicate that PDGF-C, through engagement of PDGFR and
activation of a downstream ETS translocation variant 1-mediated
CXCR4 signaling axis, promotes colorectal inflammation and
fibrosis. Accordingly, the PDGFR antagonist crenolanib has been
proposed as a candidate agent for the prevention and treatment of
radiation-induced rectal lesions (209). During pelvic RT, depletion of
Akkermansia reduces concentrations of its metabolite
3-hydroxybutyrate in the gut and circulation, limiting activation
of the intestinal cell surface receptor G-protein-coupled receptor
43. This change relieves the suppression of IL-6, thereby driving
intestinal inflammation and tissue injury (210). In addition, irradiation induces
intestinal mucosal myofibroblasts to release CCL11, which recruits
eosinophils via CCR3 and exacerbates fibrosis (104). Hypoxia can also activate VEGF
and TGF-β pathways, promoting inflammation and fibrosis and
accelerating late-stage rectal injury (211,212). Several cytokines also represent
potential therapeutic targets. For example, CCL2 has been proposed
as a biomarker of late rectal toxicity after RT in prostate cancer,
and early assessment and intervention may reduce risk (213). LR-IFN-β released by the
probiotic Lactobacillus reuteri can alleviate
gastrointestinal acute radiation syndrome after total abdominal
irradiation (214). In
addition, the microbial metabolite indole-3-carboxaldehyde can
protect the intestine from radiation injury by activating Aryl
hydrocarbon receptor/IL-10/wingless-related integration site 3
signaling and by increasing the abundance of probiotic bacteria
(215).
Radiation-induced oral mucositis is a common
toxicity of RT for head and neck tumors, with an incidence ranging
from 26.4 to 100% (216,217).
Clinically, oral mucositis presents with erythema and ulceration in
the acute stage and can evolve into persistent chronic injury,
substantially compromising quality of life (218,219). Oral mucositis development is
closely linked to cytokine network dynamics (Fig. 8). RT damages mucosal cell DNA and
generates ROS, triggering the release of DAMPs (220). These signals activate TLR,
NF-κB and MAPK pathways, drive the secretion of pro-inflammatory
cytokines including TNF-α, IL-1β and IL-6, and increase apoptosis
and inflammation (218,220,221). Oral dysbiosis can further
enhance DAMPs signaling, sustaining epithelial NF-κB activation and
cytokine production (222,223). During progression, M1
macrophages accumulate in the submucosa and secrete TNF-α and
IL-1β, amplifying inflammation (224). CD4+ T-cells
influence the disease course through modulation of the balance
among Th1, Th17 and Treg-cell subsets (225,226). In the recovery phase, M2
macrophages predominate and support tissue repair (227). Based on these mechanisms,
multiple interventions have been evaluated. Melatonin reduces
pro-inflammatory cytokine expression by scavenging ROS and
inhibiting NF-κB signaling. Mouthwash and gel formulations have
reduced the incidence of severe mucositis by a ~34% in clinical
studies (228). Chlorhexidine
mucosal patches reduce pro-inflammatory cytokine levels through
activation of macrophage α2 receptors, and a phase II trial
reported a reduced incidence of severe mucositis (229,230). Pentoxifylline inhibits TNF-α
production and, when combined with vitamin E, can shorten mucositis
duration (231,232). Recombinant human IL-11
(rhIL-11) has been evaluated to reduce ulcer severity and
accelerate healing by promoting mucosal repair (233,234). Curcumin has also been reported
to reduce pain and clinical severity through inhibition of TNF-α
(233-237). Photobiomodulation can
accelerate mucosal repair by modulating cytokine activity and
promoting angiogenesis (238,239) and has been recommended for
prevention by the Multinational Association of Supportive Care in
Cancer and International Society of Oral Oncology guidelines with
level I to II evidence (240,241). Future work should evaluate
cost-effectiveness in larger clinical trials and integrate virtual
screening to develop specific cytokine inhibitors for prevention
and treatment (242,243).
Radiation-induced liver disease (RILD) is a serious
complication of RT for upper abdominal and thoracic tumors and can
limit the broader use of RT (244,245). RT can increase inflammatory
cytokine levels and promote the infiltration of immune cells,
leading to tissue fibrosis and hepatic dysfunction (Fig. 9) (246). However, immunoregulatory
mechanisms in RILD remain incompletely defined. Pyroptosis is an
inflammatory form of programmed cell death mediated by gasdermin D
(GSDMD) that can reshape the immune microenvironment through the
release of intracellular contents and cytokines (247-250). In a murine RILD model, RT
increases hepatocellular expression of full-length GSDMD (GSDMD-FL)
and its N-terminal fragment (GSDMD-N). This process promotes CXCL1
transcription through activation of STAT5A, while GSDMD-N pore
formation facilitates CXCL1 release. The resulting CXCL1 signaling
recruits neutrophils and exacerbates liver injury. Genetic deletion
or pharmacologic inhibition of GSDMD and neutralization of CXCL1
can alleviate radiation-induced liver injury (251). Accordingly, pharmacologic
approaches such as disulfiram that suppress both GSDMD-FL and
GSDMD-N have been proposed as targeted strategies to prevent RILD
(252-255).
RILD pathogenesis also involves complex cytokine
network regulation. Ionizing radiation activates the DNA damage
response through direct DNA damage and ROS bursts, initiating ATM
and ATR signaling and MAPK cascades, including ERK/JNK/p38. These
events promote autocrine growth factor release, including TGF-α and
TNF-α, radiation-induced bystander effects and inflammatory
responses (256-259). Hepatic non-parenchymal cells
act as key effector populations. After irradiation, Kupffer cells
secrete TNF-α, which drives inflammatory monocyte infiltration
through TLR4/NF-κB signaling, inducing hepatocyte apoptosis and
secondary injury (260-264). In parallel, sinusoidal
endothelial cells undergo apoptosis and lose fenestrae, causing
microcirculatory disturbance and promoting the secretion of
fibronectin EIIIA, which activates hepatic stellate cells (265,266). Activated hepatic stellate cells
respond to TGF-β1 signaling by increasing collagen synthesis
through the TGF-β1/Smad/connective tissue growth factor axis and by
suppressing extracellular matrix degradation, resulting in
radiation-induced liver fibrosis (267-271). Radiation-induced senescent
cells can also secrete pro-inflammatory factors such as IL-6
through the SASP, further worsening the microenvironment (272,273). Translational studies have
focused on targeting cytokine pathways implicated in these
processes. In animal studies, inhibiting Kupffer-cell function
reduces TNF-α release and alleviates sinusoidal endothelial cell
apoptosis and acute liver injury (260,274). Approaches targeting TGF-β1,
including antisense oligonucleotides and small-molecule inhibitors
such as pirfenidone, can suppress fibrotic signaling and improve
radiation-induced liver fibrosis (271,275). Natural antioxidants, including
curcumin and resveratrol, can modulate pathways such as nuclear
factor erythroid 2-related factor 2/Kelch-like ECH-associated
protein 1 and miR-34a-sirtuin 1 to suppress ROS/TNF-α/NF-κB-driven
inflammatory axes, thereby reducing oxidative stress and fibrotic
progression (276-279). Mesenchymal stem cell therapy
can inhibit TGF-β/Smad signaling and promote tissue repair through
the secretion of anti-inflammatory mediators such as hepatocyte
growth factor (266,280). However, targeted therapeutics
remain limited. Future work should integrate precision RT
approaches such as stereotactic RT and explore combinations with
immune checkpoint inhibitors to balance efficacy and hepatotoxicity
(281).
Given the role of IFN-I in RT-induced innate and
adaptive immunity, IFN-I has been explored as a therapeutic lever
in cancer (282). Early studies
showed that IFN-γ+CD8+ T-cells can increase
radiosensitivity in hypoxic tumors (283). RT-induced IFN-β can remodel the
antitumor immune microenvironment and has been associated with
improved disease-free survival in lung cancer (284). Preclinical murine tumor studies
indicated that loss of IFN signaling in the host or tumor after RT,
with or without immune checkpoint blockade, weakens local and
systemic immune responses (66,67,285). By contrast, a study in a murine
tumor model suggested that persistent IFN signaling can contribute
to resistance to immune checkpoint therapy (87). Tumor cells with high Argonaute 2
(AGO2) expression may suppress responsiveness to IFN-γ through a
negative feedback loop involving AGO2/protein tyrosine phosphatase
non-receptor type 6/STAT1, thereby promoting immune evasion.
Targeting this pathway has been proposed for tumors with high AGO2
expression (286). These
findings support a practical clinical strategy based on patient
stratification. Baseline and early post-RT IFN-related gene
signatures and circulating cytokine profiles can be used to
classify tumors by their IFN-I signaling state (83,91,213,287). In tumors with low baseline
IFN-I signaling, STING agonists or IFN-I agonists may be considered
to enhance priming (66,67,77,131,282). In tumors with chronically high
IFN-I signaling, the risk of tolerance and resistance should be
evaluated, and shortened exposure or intermittent dosing may be
more appropriate (83,85-88). This approach treats IFN-I as a
modifiable system variable rather than a single-direction target
(131).
Mechanistically, the cGAS-STING pathway lies
upstream of RT-induced IFN-β production and links dendritic cell
cross-presentation with CD8+ T-cell priming, forming a
central axis from innate sensing to adaptive immunity. STING
signaling is required for effective adaptive responses in multiple
models. Loss or inhibition of YTHDF1 reduces cathepsin A- and
cathepsin B-mediated STING degradation, restores STING stability,
increases irradiation-induced IFN-β secretion and dendritic cell
antigen cross-presentation, and promotes CD8+ T-cell
cytotoxicity, thereby strengthening RT efficacy. Based on this
mechanism, a dendritic cell vaccine generated by YTHDF1 knockout or
treatment with the small-molecule inhibitor salvianolic acid C
enhanced the efficacy of RT alone and RT combined with PD-L1
blockade in a preclinical model (81). In addition, combining RT with the
STING agonist cGAMP can reduce radioresistance and enhance host
antitumor immunity (67).
As described above, the CCL22/CCR4 axis contributes
to immune regulation. Targeting this axis may disrupt interactions
between Treg cells and DCs, enhance tumor antigen-specific T-cell
responses and potentially synergize with PD-1 or CTLA-4 inhibitors
(108). In a murine pancreatic
cancer model, stereotactic body RT combined with locally delivered
IL-12 fusion protein remodeled the TME, increased infiltration and
activity of antitumor macrophages and CD8+ T cells and
resulted in durable tumor regression (288).
The DNA damage response network is another hub
linking immunity and RT. When DNA repair is efficient, immunogenic
cell death and cGAS-STING activation may be reduced, whereas
impaired repair can increase cytosolic DNA signaling. Esophageal
squamous cell carcinoma often exhibits radioresistance and poor
prognosis (289). Overcoming
radioresistance remains a priority, and the DNA damage response
machinery that detects and repairs radiation-induced lesions
represents a mechanistic contributor (290,291). PARP1 functions as a central
sensor protein in this network (292). PARP inhibitors can activate
cGAS/STING signaling and promote innate immune activation (74), consistent with RT-driven
cytokine-mediated adaptive immunity (42,293). Although direct links between
PARPis and specific cytokines require further definition,
mechanistic intersections are plausible and clinically relevant. In
esophageal cancer, astrocyte elevated gene-1 recruits the
deubiquitinase biquitin-specific peptidase 10 to remove K48-linked
polyubiquitination at Lys425 of PARP1, reducing PARP1 degradation
and increasing recruitment to double-strand break sites. This
mechanism enhances homologous recombination-mediated repair and
reduces radiation lethality in esophageal squamous carcinoma cells
(294). Vav guanine nucleotide
exchange factor 2 (VAV2) is another candidate target. Increased
VAV2 promotes the formation and activity of the Ku70-Ku80 complex
involved in nonhomologous end joining repair and reduces
radiation-induced DSBs. Under irradiation, VAV2 can also activate
STAT1 signaling and promote radioresistance, and the STAT1
inhibitor fludarabine can reverse this phenotype in a preclinical
model (295).
Cytokine mechanisms of radiation injury are
discussed above. Translational studies also suggest that
irradiation can activate the constitutively expressed NLR family
pyrin domain containing 3 (NLRP3) inflammasome in bone
marrow-derived macrophages, inducing pyroptosis and IL-1β
production, and contributing to tissue injury and immune-cell loss
(296). A plausible mechanism
is that irradiation activates TLRs, leading to priming and
increased NLRP3 expression, which promotes caspase-1 activation,
IL-1β processing and pyroptosis (297-299). Caspase-1-dependent pyroptosis
is not restricted to NLRP3. Other inflammasomes, including NLRP1,
NLRC4 and the DNA-sensing absent in melanoma 2 (AIM2) inflammasome,
may also contribute to radiation-associated caspase-1 activation
(298-300). Irradiation can also induce the
release of M1-type pro-inflammatory cytokines and MCP-1 (301,302), and may amplify inflammatory
cascades through DAMPs and additional inflammasome pathways,
including AIM2 (300,303). These data support targeting
NLRP3-driven pyroptosis as a strategy to reduce
radiation-associated immune-cell loss, pro-inflammatory cytokine
cascades and tissue injury.
This section also summarizes cytokine-related
clinical studies, including therapeutic targets, drug classes and
combination paradigms involving RT with or without immunotherapy,
to support the development and clinical application of
cytokine-directed agents in the RT setting (Table II) (8,304). Table III provides a concise
cross-cytokine overview of representative clinical trials grouped
by cytokine axis, cancer type, RT-containing regimen and study
focus, thereby highlighting recurring translational patterns across
IFN-, IL-2-, GM-CSF- and TGF-β-directed strategies. Several themes
emerge from these trials. TGF-β inhibition has been explored across
multiple tumor types: Fresolimumab is being evaluated in
combination with RT in metastatic breast cancer (NCT01401062) and
with stereotactic ablative body radiotherapy in early-stage
non-small-cell lung cancer (NCT02581787), while bintrafusp α, a
bifunctional TGF-β/PD-L1 inhibitor, is under investigation with RT
in esophageal squamous cell carcinoma (NCT04595149) and in
combination with SBRT and IL-12 agonist M9241 in advanced
pancreatic cancer (NCT04327986). IL-2-based strategies represent
another active area, with trials combining SBRT and high-dose IL-2
in melanoma (NCT01416831), intralesional IL-2 with RT in refractory
metastatic NSCLC (NCT03224871) and bempegaldesleukin (NKTR-214)
plus nivolumab with RT in sarcoma (NCT03282344). GM-CSF has been
combined with SBRT in stage IV NSCLC after second-line chemotherapy
failure (NCT02623595) and with RT and PD-1 inhibition in advanced
recurrent or metastatic head and neck tumors (NCT05760196).
IFN-based approaches include adjuvant IFN-α2b with postoperative RT
for metastatic melanoma (NCT00003444) and IFN-β combined with
avelumab with or without RT for Merkel cell carcinoma
(NCT02584829). Collectively, these trials reflect a broad effort to
target cytokine axes across diverse tumor histologies and RT
delivery platforms.
The efficacy of combining RT with immune checkpoint
inhibitors depends on remodeling the immune state of the TME.
Identification and modulation of key immunoregulatory factors are
therefore important for optimizing combination strategies. IFN-I
signaling induced by irradiation is required to initiate systemic
antitumor immunity. For instance, in IFN-I receptor knockout
models, RT shows minimal efficacy, suggesting that IFN-I signaling
may have predictive value for response to RT combined with
immunotherapy (66,67). Clinically, IFN-related gene
signatures may help estimate radiosensitivity and the likelihood of
benefit from immunotherapy (83). This pathway also offers
actionable targets. STING agonists and PARPis can amplify
RT-induced innate immune signaling and may enhance responses to
PD-1 or PD-L1 blockade (77). In
parallel, TAMs and macrophage-mediated immunosuppression contribute
to radioresistance. After RT, tumors can exhibit increased
macrophage infiltration and M2 polarization, and chemokines such as
CCL2 produced in this setting can recruit MDSCs and weaken
antitumor immunity (92,94). High macrophage density and
hyperactivation of the CCL2/CCR2 axis have been associated with
poor outcomes in RT-immunotherapy combinations and may serve as
candidate biomarkers of response. Interventions targeting this
mechanism have shown benefit in preclinical models. CSF1R
inhibitors can deplete intratumoral macrophages, improve local
control and delay recurrence when combined with RT (35-37,154). Blockade of CCL2/CCR2 signaling
can reduce macrophage chemotaxis, remodel the TME and increase
radiosensitivity (95,153). These findings support an
approach in which IFN signaling and macrophage-related cytokine
profiles are assessed to guide the selection of adjunctive
immunomodulatory interventions.
Mechanism-based prevention and management of
RT-related toxicity is a key translational priority while pursuing
antitumor efficacy. Radiation-induced lung injury is linked to
dysregulated immune responses. RT can trigger an acute inflammatory
cascade in the lung with early increases in mediators such as IL-1,
TNF-α and IL-6, whereas persistent inflammatory signaling
contributes to chronic fibrotic remodeling (188,190-192). Excessive STING activation can
have context-dependent effects. In normal lung tissue, STING
signaling can exacerbate fibrosis by promoting CCR2-dependent
monocyte recruitment and M2 macrophage polarization (195). A preclinical study indicated
that CCR2 deficiency or pharmacologic blockade reduces inflammatory
cell infiltration and capillary damage and can reduce lung injury
after irradiation (96). These
findings support monitoring of inflammatory biomarkers such as IL-6
and TGF-β during RT to identify patients at increased risk and to
consider the timely use of anti-inflammatory or anti-fibrotic
interventions to limit progression from acute inflammation to
chronic injury (189,191). Radiation-induced liver injury
can also involve an innate immunity-driven inflammatory loop.
Ionizing radiation can activate the NLRP3 inflammasome in Kupffer
cells and induce pyroptosis, leading to the release of IL-1β and
other inflammatory mediators and exacerbating parenchymal injury
(250,251). Targeting
inflammasome-associated pyroptosis has therefore been proposed as
an interventional strategy. In preclinical models, disulfiram
inhibits GSDMD-mediated pyroptosis and reduces irradiation-induced
hepatocyte injury and neutrophil infiltration (252,254). In clinical practice, liver
function and relevant inflammatory biomarkers should be monitored
during RT, and hepatoprotective and anti-inflammatory measures
should be implemented when abnormalities are detected to prevent
irreversible decompensation (244,245).
Oral mucositis, a frequent consequence of head and
neck RT, reflects a cascade of immune responses initiated by
epithelial injury. After disruption of the oral mucosal barrier,
exposed basal cells and microbial products can activate pathways
such as NF-κB, induce the release of pro-inflammatory mediators
including TNF and IL-6, and promote neutrophil and macrophage
infiltration, leading to ulceration and pain (220,221). Consistent with this mechanism,
peripheral blood inflammatory markers correlate with mucositis
severity, and routine monitoring of TNF and IL-6 may provide an
adjunctive tool for assessing mucosal damage during treatment
(221). Multiple randomized
controlled trials have evaluated targeted interventions, including
topical recombinant human IL-11 mouthwash to promote mucosal
regeneration, anti-inflammatory mouth rinses and photobiomodulation
to accelerate ulcer healing (232,236,237). Photobiomodulation, supported by
its anti-inflammatory and pro-healing effects, has been recommended
by clinical guidelines as a first-line measure for preventing and
managing radiation-induced oral mucositis (239,240). Thus, mechanism-guided
monitoring and intervention may reduce the incidence and severity
of RT-related toxicities.
The selection of the RT modality and parameters can
alter immune trajectories and toxicity profiles through effects on
cytokine networks, providing an additional dimension for clinical
optimization. Hypofractionated regimens such as SBRT generate
systemic immune and inflammatory environments that can differ from
conventional fractionation because of high conformality and steep
dose gradients (305).
High-dose irradiation-induced cellular damage leads to the release
of ROS, inflammatory mediators and adhesion molecules that can
function as danger signals and enhance immune responses (306). In a clinical study evaluating
SBRT combined with IL-2 in metastatic melanoma or renal cell
carcinoma, the combination increased the frequency of proliferating
CD4+ T cells and early activated effector memory
phenotype cells, with an objective response rate exceeding
historical benchmarks (307).
Preclinical work has also evaluated SBRT combined with cytokine
modulation in pancreatic cancer models. In that setting,
IL-12-related effects depend on IFN-γ signaling and have been
linked to the reversal of T-cell exhaustion (308). A comparative study of RT
techniques from a cytokine perspective reported that
hypofractionated stereotactic RT reduced IL-10 and IL-17 with
limited effects on IL-1α, IL-6, macrophage inflammatory protein 1α
and TNF-α. These patterns were interpreted as consistent with lower
pulmonary toxicity and limited systemic immune perturbation. By
contrast, IMRT altered multiple cytokine pathways associated with
both antitumor and protumor effects, and outcomes may depend on
individual and protocol-specific factors (287).
FLASH RT delivered at ultra-high dose rates has
been reported to reduce normal tissue injury while maintaining
antitumor activity in preclinical models. In animal studies, FLASH
RT reduces free radical accumulation and endothelial injury in
normal tissues and suppresses the production of multiple
pro-inflammatory and profibrotic cytokines. Compared with
conventional RT, FLASH reduces mediators such as TGF-β and IL-1β in
lung tissue, alleviates lung injury and promotes CD4+
T-cell secretion of reparative cytokines, including IL-10 and
IL-22, which may support tissue regeneration (62,63). Proton therapy improves dose
distribution and can reduce normal tissue exposure. When combined
with immunotherapy, proton therapy has been associated with
increased intratumoral IFN-γ+ T cells and reduced TGF-β
signaling, potentially enhancing systemic antitumor immunity
(64). These observations
suggest that dose, fractionation, dose rate and irradiation field
should be considered controllable variables that influence the
balance between immune activation and immunosuppression, and
between antitumor efficacy and normal tissue toxicity.
In summary, integrating mechanistic understanding
of RT-induced immune signaling with clinical decision-making can
support measurable and adjustable therapeutic strategies. Candidate
approaches include profiling cytokines and immune-cell composition,
selecting RT regimens based on patient-specific immune features and
incorporating targeted agents to modulate detrimental inflammatory
or immunosuppressive pathways. These steps may enhance RT-driven
antitumor immunity while limiting normal tissue injury (192). With improved mechanistic
resolution and clinically implementable monitoring and intervention
strategies, RT can be developed as a component of systemic
immunomodulatory treatment, supporting individualized
radioimmunotherapy.
Not applicable.
SZ, YJ, JF, MG, YW and CD collected the relevant
literature and drafted the manuscript. CD designed the review
framework and revised the manuscript. Data authentication is not
applicable. All authors read and approved the final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
This study received funding from the following sources: The Key
Research Project of Jiangsu Provincial Health Commission (grant no.
ZDB2020022) and the Guidance Science and Technology Plan Project
for Social Development of Zhenjiang City (grant no. FZ2023049).
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