Radiotherapy and cytokines: A systems view of immunotherapy and toxicity (Review).

Introduction

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, 223 Ra-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 ).

IFNs

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.

Collectively, IFN-I has a dual role in RT responses ( Fig. 2 ). IFN-I can enhance antitumor immunity by activating dendritic cells and promoting CD8 + T-cell cross-priming through the cGAS/STING/IRF3 pathway. However, sustained or excessive IFN-I activity may increase PD-L1 expression, accelerate YTHDF1-dependent STING turnover and activate additional tolerance programs that ultimately constrain effector T-cell function.

Chemokine family

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 ).

Pro- and anti-inflammatory cytokines

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 ).

The critical role of macrophages

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.

Mechanisms of RBI

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

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

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

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 injury

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 ).

Translational and clinical implications

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.

Discussion

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.

Acknowledgements

Not applicable.

Availability of data and materials

Not applicable.

Authors' contributions

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.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Abbreviations

radiotherapy

tumor microenvironment

tumor-associated macrophage

dendritic cell

cytotoxic T lymphocyte

myeloid-derived suppressor cell

cancer-associated fibroblast

type I interferon

type I IFN receptor

tumor necrosis factor

interleukin

transforming growth factor β

C-C motif chemokine ligand

C-X-C motif chemokine ligand

C-C chemokine receptor

reactive oxygen species

double-stranded DNA

cyclic GMP-AMP synthase

stimulator of interferon genes

nuclear factor κB

signal transducer and activator of transcription

mitogen-activated protein kinase

DNA damage response

Toll-like receptor

radiation-induced liver disease

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