As with any inflammation process, RT-induced inflammation starts with acute inflammation and then progresses into chronic inflammation. Activated DCs induce inflammatory responses via cross-presenting tumor antigens to prime tumor-containing CD8+ T cells, polarizing immune cells into tumor suppression, or stimulating NK cells to sustain T-cell responses. However, if acute inflammation persists, it transitions into chronic inflammation; cancer cells not only hijack DCs to inhibit tumor antigen presentation, preventing innate and anti-tumor immunity, but also recruit extensively more immunosuppressive cells, providing a rich proangiogenic and pro-tumoral environment [14].

Inflammatory toxicity is a common adverse effect of RT, driven by both local tissue damage and systemic immune responses. As our understanding of radiation-induced inflammation deepens, a variety of circulating biomarkers have emerged as valuable tools for assessing the extent and severity of this toxicity, particularly due to their accessibility in peripheral blood. Among these, C-reactive protein (CRP) is a liver-derived acute-phase protein upregulated by proinflammatory cytokines such as IL-6, and reflects systemic inflammatory burden, while interleukin-1 receptor antagonist (IL-1Ra) acts as a natural inhibitor of IL-1 signaling, often elevated in response to excess proinflammatory cytokine activity. On the other hand, the neutrophil-to-lymphocyte ratio (NLR) captures the balance between innate immune activation and adaptive immune suppression, with elevated NLR indicating neutrophil-driven inflammation and reduced lymphocyte-mediated anti-tumor immunity. Similarly, yet distinctively, the monocyte-to-lymphocyte ratio (MLR) reflects chronic inflammation mediated by monocyte activation and a concurrent reduction in lymphocyte-driven anti-tumor immunity. Together, these biomarkers offer mechanistic insight into the inflammatory processes underlying radiation-related side effects, including fatigue, tissue injury, and poor clinical outcomes.

Previous studies have identified inflammatory biomarkers such as CRP and IL-1Ra as key downstream indicators of proinflammatory cytokine network activation. These markers not only reflect systemic inflammation but have also been significantly associated with fatigue during RT for breast and prostate cancers [15]. This association is likely due to the heightened release of proinflammatory cytokines—including IL-1β, IL-6, and TNF-α (tumor necrosis factor-alpha)—not only within the tumor microenvironment but also in adjacent healthy tissues, a consequence of the limited precision in conventional radiation techniques. These findings underscore the relevance of CRP and IL-1Ra as biologically meaningful indicators of radiation-induced inflammatory toxicity and their potential value in predicting therapy-related fatigue.

In addition, MLR has been identified as a potential indicator of radiation-induced toxicity and patient prognosis. In a study by Tanaka et al. [16], patients with elevated MLR exhibited a significantly lower 6-month overall survival (OS) rate (49.8%) compared to those with lower MLR values (79.8%). While this finding underscores the prognostic value of MLR, it is important to consider the study population—patients with stage IV lung cancer receiving palliative radiotherapy. The inherently aggressive nature of the disease and limited life expectancy in this group, though a sobering clinical reality, impose constraints on long-term biomarker analysis and mechanistic exploration. Although the study provides valuable insight into MLR as a prognostic tool in the palliative care setting, further investigations involving longer-term follow-up in more diverse patient populations may be necessary to fully elucidate the biological significance of MLR in radiation-induced inflammatory toxicity.

Interestingly, a study by Takaoka et al. [17] investigating helical tomotherapy for liver metastases originating from pancreatic cancer has underscored the potential utility of inflammatory biomarkers as prospective prognostic indicators. The authors found that low pretreatment levels of NLR and MLR were paradoxically associated with poorer clinical outcomes, whereas lower MLR was otherwise typically correlated with improved OS rates in other contexts. This finding further reinforces the prognostic relevance of immune-based markers such as NLR and MLR in understanding cancer progression and guiding therapeutic decision-making.

Collectively, inflammatory biomarkers such as CRP, IL-1Ra, NLR, and MLR offer a valuable snapshot of the dynamic interplay between pro- and anti-inflammatory forces during RT. Elevated levels may reflect an exaggerated immune response involving both malignant and surrounding healthy tissues, contributing to adverse outcomes such as fatigue, reduced survival, and overall poor prognosis. The routine monitoring of these biomarkers could facilitate early detection of radiation-induced toxicity and inform personalized treatment strategies. Nonetheless, numerous questions remain in this field—particularly regarding the optimal patient populations for long-term follow-up. Carefully designed prospective studies with extended observation periods will be essential for bridging existing knowledge gaps. Importantly, future research integrating these hematologic biomarkers with cytokine profiling may further elucidate their predictive utility and support the development of inflammation-targeted interventions in radiotherapy.

Previous studies have discovered that RT can induce ICD of irradiated tumor cells. DAMPs such as proteins, nucleic acids, and metabolites leak from damaged, dying cells. DCs and other APCs are activated by binding to these DAMPs. After APC and DC activation, they mediate anti-tumor T-cell responses [18]. Additionally, the innate immune response plays a significant role in self-amplified anti-tumor response. Activated anti-tumor T-cells will migrate to the irradiated site, inducing apoptosis in the damaged tumor cells. This will result in increased DAMPs concentration due to more tumor cells being damaged and dying. These DAMPs will induce more DCs and APCs at the site, increasing the immune response [19]. Adaptive immune response mediated by T-cells prevents metastasis and induces anti-tumor immunity by killing distant tumor cells after developing anti-tumor immunity [9].

Although previous studies have shown the benefits of having an innate immune response after RT through ICD, Wu et al. [20] demonstrated that radiation can induce inflammation through the IL-6/STAT3 signaling pathway, helping tumor cells facilitate invasion and survival after therapy. Additionally, studies by Culig and Puhr [21] have shown that silencing IL-6 using siRNA prevents tumor recurrence following radiotherapy in prostate cancer and increases tumor cells’ sensitivity to radiation.

Chronic inflammation is known as one of the key players in cancer development [22]. Previous studies done by Greten and Grivennikov [23] in 2019 demonstrated that cancer-associated genes recruit and activate pro-inflammatory cells, leading to tumor progression. Browning et al. [24] in 2018 showed that inflammation induces pro-inflammatory IL-6, which then activates the JAK/STAT3 pathway for malignant tumor proliferation. Studies done by Theoharides [25] in 2008 demonstrated that the oncogenic MYC gene induces the recruitment of mast cells, which are responsible for angiogenesis and expansion to tumor sites.

Furthermore, previous studies have shown that RT can reinforce the harmful side effects of inflammation. Zhang et al. [26] demonstrated that RT can potentially induce a cytokine storm (Figure 2). The three pathways they demonstrated are: (1) pro-inflammatory responses initiated by DAMPs interacting with PRRs; (2) the release of chemokines like CXCL16 and CCL5; and (3) the activation of neoantigen presentation alongside the cGAS-STING signaling pathway. Previous studies, done by Schaue et al. [27], have demonstrated that radiation affects both acute and chronic inflammatory disease.

Different organs respond differently to RT due to variations in their cell types and immune response programming. Evidence suggests that RT-induced inflammation activates endothelial cells to produce inflammatory mediators. As a result, the CD11/CD18 on leukocytes is up-regulated, increasing NF-κB-dependent endothelial cell adhesion molecule (CAM) expression. This will assist the leukocyte adhesion and reinforce the extravasation of inflammatory cells into the GI (gastrointestinal) tissues, thus inducing organ damage [28].

Unlike the GI tract’s reliance on endothelial cells, the CNS (central nervous system) depends on microglia to detect and respond to radiation. Upon ionizing radiation (IR), microglia swiftly engage neurons, astrocytes, and oligodendrocytes to orchestrate CNS-specific defenses—modulating the blood-brain barrier (BBB), controlling peripheral immune cell entry, and inhibiting neurogenesis [29]. Although IR universally activates DNA damage pathways (NF-κB, CREB, AP1) and upregulates IL-1β, TNF-α, COX2, and MCP1, the CNS’s inflammatory response is uniquely gated by microglial expression of tight junction proteins like claudin5, which more stringently limits peripheral infiltration than in other tissues [30]. Radiation also disrupts the anatomical support between neural progenitors and their microvasculature; the ensuing microglial inflammation alone suffices to sever neurovascular contacts and suppress stem cell function [31]. Coupled with the brain’s inherently poor regenerative capacity, these effects explain the progressive deficits in memory, attention, and executive function observed months to years after cranial irradiation [32].

Skin is one of the most common sites to experience radiation-induced damage after RT. Previous studies have revealed that 95% of the patients who were treated with RT experienced skin changes [33]. In part of the skin’s innate response, Langerhans cells reside in the epidermal layer, and DCs and resident T cells reside in the dermal layer. They have a significant role in initiating immune responses against barrier injury. Antigen-specific effector T cells, such as CD4+, CD8+, and Treg, are responsible for adaptive immunity. There are also unconventional lymphocyte subsets, such as αβ and γδ T cells, which are considered part of innate immunity [34]. Radiation dermatitis refers to skin inflammation resulting from exposure to IR, commonly occurring as a side effect of RT or, less frequently, due to accidental nuclear exposure. Studies have shown that radiation-induced skin damage is driven by IL-17—producing γδ T cells and innate lymphoid cells. This process involves increased expression of IL-1β and IL-23 at the site of injury, which subsequently promotes keratinocyte hyperproliferation [35]. This hyperproliferation of the keratinocytes will induce an imbalance in the keratinocytes in the skin layer, which ultimately contributes to skin damage.

While resident DCs and unconventional lymphocytes like γδ T cells play a significant role in immune response to RT in the skin system, the respiratory system relies heavily on innate immune cells, particularly macrophages. Previous studies on mice demonstrated that radiation damage activates cGAS-STING signaling through CCL2 and induces the M1 polarization of microphages. The M1 macrophages secrete proinflammatory mediators such as cytokines, ILs, and IFNs, ultimately leading to the development of radiation pneumonitis [36].

Modern photon-based RTs triumph in their increasingly refined precision, which directly correlates with reduced inflammation and toxicity—two critical determinants of both patient tolerability and survival.

For instance, SBRT demonstrates high precision coupled with high-dose delivery over a limited number of fractions. In the study by Van’t Land et al. [37], the systemic immune-inflammation index (SIII)—a composite biomarker derived from neutrophil, platelet, and lymphocyte counts—was used to assess immune response. While no significant group-wide change in SIII was observed post-SBRT, patients who experienced a reduction in SIII demonstrated markedly improved OS (24.0 vs. 11.6 months; P < 0.036) [37]. This suggests that SBRT’s precision may limit unintended immune activation, and SIII may serve as a useful prognostic indicator to guide candidate selection and predict response.

By contrast, 3D-CRT—an earlier-generation photon-based modality—relies on static beam shaping and lacks the adaptive modulation seen in techniques like SBRT. Theoretically, its fixed geometry and broader treatment margins render it less precise than SBRT, potentially exposing more surrounding healthy tissues to radiation and increasing the risk of inflammatory toxicity. However, recent findings suggest a more nuanced profile: in a study on advanced bladder cancer, 3D-CRT combined with chemotherapy resulted in significantly lower post-treatment IL-6 levels than chemotherapy alone (63.43 ± 7.95 vs. 132.75 ± 16.12 ng/L), indicating a capacity to attenuate systemic inflammation [38]. More importantly, this anti-inflammatory effect translated into improved survival outcomes: the 1-year survival rate in the 3D-CRT combination group was 76.19% compared to 47.62% in the chemotherapy-only group, and the 2-year survival rate was 47.62% vs. 19.05%, respectively [38].

This outcome highlights a potential therapeutic synergy. While 3D-CRT alone may theoretically induce more collateral damage than other precision modalities such as IMRT (Intensity-Modulated Radiation Therapy), IGRT (Image-Guided Radiation Therapy), SBRT, or even Proton Beam Therapy (PBT), its role alongside chemotherapy appears to blunt harmful cytokine surges. Unlike the other therapies typically used as standalone treatments, 3D-CRT may derive greater utility when employed as a supportive adjunct—leveraging its spatial coverage to enhance tumor response, while relying on systemic agents to help control treatment-induced inflammation.

IMRT represents a significant leap in conformal dosing, enabling selective targeting even in anatomically complex regions. In a prospective analysis of patients with advanced non-small-cell lung cancer, IMRT significantly reduced the incidence of grade ≥ 3 pneumonitis compared to 3D-CRT (3.5% vs. 7.9%; P = 0.039), despite being applied to patients with larger and more advanced tumors [39]. This reduction in treatment-induced lung inflammation highlights the clinical significance of IMRT’s superior spatial precision, which allows for precise sculpting of dose away from critical normal lung tissue, thereby minimizing collateral damage. This finding underscores IMRT’s unique clinical utility in managing complex tumor presentations, particularly those located near critical structures such as the heart, esophagus, or major airways. While IMRT and SBRT share similar beam-shaping and image-guidance technologies, IMRT holds a distinct advantage in treating irregularly shaped or voluminous tumors. This is likely due to its ability to gradually deliver radiation over a larger number of fractions, allowing for effective dose distribution with reduced risk to surrounding normal tissues. In contrast, SBRT’s strength lies in its ultra-high-dose, high-precision delivery, which, although extremely effective for small, well-defined lesions, may not be suitable for larger or anatomically complex targets. The IMRT data in advanced lung cancer thus not only support the principle that greater spatial precision reduces toxicity but also illustrate the importance of fractionation flexibility in balancing tumor control and normal tissue preservation.

Last but not least, IGRT builds upon IMRT by integrating real-time imaging corrections to account for inter- and intrafractional motion. In a meta-analysis involving over 5,000 prostate cancer patients, IGRT was associated with significantly reduced rates of acute and late toxicity across multiple systems—GI [RR (relative risk) = 0.55, P = 0.007], GU (genitourinary) (RR = 0.82, P = 0.006), and late GI complications [HR (hazard ratio) = 0.25, P = 0.03] [40]. The data imply that IGRT’s precision extends beyond planning to execution, minimizing healthy tissue exposure and allowing for tighter margins without compromising safety.

In summary, the progression from 3D-CRT to IMRT, SBRT, and IGRT illustrates a clear trajectory: as spatial and temporal precision improve, inflammation-induced toxicity tends to decline, leading to improved patient outcomes and greater treatment tolerability. A common misconception, however, is the treatment of IGRT as a standalone radiation modality. In reality, IGRT serves as a powerful adjunctive technology whose primary function is to enhance the precision of other radiotherapy modalities by enabling real-time imaging and positional verification during treatment delivery.

Notably, the integration of IGRT benefits different modalities to varying degrees. While its impact on 3D-CRT is relatively limited—due to the broader treatment fields and static beam shaping inherent to that technique—its combination with IMRT and SBRT significantly amplifies their precision and safety profiles. This further reinforces why 3D-CRT, though once standard, is increasingly considered less favorable or even obsolete, not only for its limited responsiveness to IGRT enhancement, but also due to its higher risk of damaging healthy tissues. This further reinforces why 3D-CRT, though once standard, is increasingly considered less favorable or even obsolete, not only for its limited responsiveness to IGRT enhancement, but also due to its higher risk of damaging healthy tissues. However, it is important to note that the perceived precision hierarchy among IMRT, SBRT, and IGRT should not be oversimplified. While the overall trend reflects advancements in targeting accuracy, IMRT and SBRT each serve distinct roles based on tumor geometry, location, and clinical goals. SBRT offers unparalleled precision for small, well-defined lesions, whereas IMRT excels in conformal treatment of irregular or anatomically complex tumors. In this context, precision must be evaluated alongside tumor-specific characteristics rather than ranked in isolation. Importantly, precision alone does not determine clinical suitability; the anatomical complexity, size, and shape of the tumor often dictate whether IMRT or SBRT is more appropriate. Yet in both cases, the addition of IGRT confers substantial advantages by reducing setup uncertainties and enabling tighter treatment margins.

Even though this review has primarily examined photon-based modalities as standalone treatments, the observed benefits of integrating IGRT raise a critical question: Could the addition of IGRT to proton therapy similarly enhance its therapeutic precision by incorporating real-time image guidance? This possibility sets the stage for the emerging role of proton therapy as a highly precise modality and explores how it compares—both in targeting accuracy and immune response profiles—to its photon-based counterparts.

Photon-based therapies like SBRT, 3D-CRT, IMRT, or IGRT have revolutionized cancer treatment, but they still pose a challenge due to the unintended radiation exposure to nearby healthy tissues. In contrast, proton therapy stands out with its remarkable precision, reducing collateral damage and presenting a compelling alternative. A study by Li et al. [41] explored the effects of stereotactic body proton therapy (SBPT) compared to SBRT. Interestingly, SBPT cases showed a more rapid inflammatory response in the lungs than SBRT. While this heightened inflammatory reaction doesn’t appear to cause additional cellular toxicity or negatively affect patient outcomes, it could unlock exciting opportunities for synergy with immunotherapies, such as immune checkpoint inhibitors (ICIs). This accelerated immune response might offer a therapeutic edge in combining SBPT with ICI-based treatments.

Similarly, a study done by Davuluri et al. [42] has also shown the benefit of PBT compared to IMRT in esophageal cancer patients. This study focused on the measurement of lymphocyte count and divided it into 4 grades, 4 being the worst. The importance of immunity and lymphocytes has made lymphopenia a crucial topic when studying different cancer treatments. The study has shown a significant proportional association between mean body dosage (MBD) and grade 4 absolute lymphocyte count (G4 ALC) nadir. Likewise, patients with G4 ALC nadir had a higher MBD than those without (12.7 Gy vs. 10.8 Gy, P < 0.001). At last, the discovered patients treated with PBT had a significantly lower MBD (8.0 Gy vs. 13.2 Gy, P < 0.001) and a higher likelihood of having an MBD < 10 Gy (88.6% vs. 11.4%, P < 0.001) than did patients treated with IMRT concluded the benefits of proton ration therapies do not only reside in the lower MBD but more importantly in its protection toward host’s immunity.

Although normal tissue toxicity remains a major dose-limiting factor in RT and a significant contributor to long-term complications in cancer survivors, effective treatment options to mitigate these side effects are still limited. Currently, anti-inflammatory drugs are among the most commonly used interventions. At the same time, ongoing research is exploring novel therapeutic strategies to counteract radiation-induced toxicities. These approaches focus on reducing RT-induced apoptosis through various pathways, restoring post-radiation redox balance, and directly targeting inflammatory and fibrogenic signaling cascades [43].

When it comes to apoptosis, we cannot avoid talking about p53. In a study investigating the inhibition of p53-dependent apoptosis, Wang et al. [44] identified PUMA as a key p53 target that mediates radiation-induced apoptosis through a cell-intrinsic mechanism. Their findings further highlight CHIR99021, a GSK-3 inhibitor, as a potent radioprotective agent, offering a potential strategy to mitigate radiation-induced cellular damage. Although Wang et al. [44] could not directly assess radiation responses in human subjects, they examined the effects of CHIR99021 in human intestinal cultures derived from two unrelated donors. These cultures contained all differentiated epithelial lineages, providing a relevant model for studying intestinal regeneration. Their findings were promising: enteroid formation significantly improved 10 days after exposure to 5 Gy radiation in cultures treated with CHIR99021. Additionally, blocking PUMA induction led to a notable increase in the expression of key intestinal stem cell (ISC) markers, including Olfm4, Lgr5, Ascl2, and CD44. These molecular changes were accompanied by a significant reduction in apoptosis, decreased DNA damage, and enhanced cell proliferation, highlighting CHIR99021’s potential as a radioprotective agent.

In addition, free radicals are another main reason for cell damage, even in healthy individuals. Therefore, modulating these free radicals to restore redox equilibrium to reverse normal tissue injury is another critical mitigation for post-radiation patients. A study done by Mahmood et al. [45] discovered the benefit of a genistein diet toward radiation-induced oxidative damage in rats. They utilized the levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative damage in the DNA, and levels of malondialdehyde (MDA), a measure of lipid peroxidation. As expected, the treatment group showed a decreasing trend in 8-OHdG, and MDA concentration was also significantly decreased by the genistein diet. Furthermore, a higher survival rate of irradiated rats was associated with the treatment group, where a proportion of the control group had to be euthanized due to excessive morbidity between 6–18 weeks; however, almost all rats in the treatment group survived to the end of the study at 36 weeks. Even though genistein is only one substance dedicated to restoring redox equilibrium, it also sheds light on the inflammatory and fibrogenic pathways contributing to tissue damage post-RT, supporting research in direct signal intervention targeting inflammatory and fibrogenic signals.

Lastly, an effective substance, ambroxol, is a great protective agent against the transforming growth factor beta 1 (TGF-β1) and TNF-α, studied by Xia et al. [46]. TGF-β1 is believed to have the closest relationship with the generation of radiation lung fibrosis, significantly diminishing patients’ quality of life. The study showed a significant decrease in the level of TGF-β1 in the treatment group compared to the control. In addition, ambroxol was also observed to significantly abolish the production of post-radiation TNF-α. The dual effect, on early-phase radiation pneumonitis (TNF-α) and late-phase lung fibrosis (TGF-β1), makes ambroxol a novel supplement for RT patients.

In a recent comparative study of proton radiotherapy (PT) versus photon therapy, Baumann et al. [47] found no significant difference in disease-free or OS between the two modalities. However, they observed a two-thirds reduction in adverse events associated with unplanned hospitalizations of the proton chemoradiotherapy cohort, even though that cohort was significantly older and had less favorable Charlson-Deyo comorbidity scores.

Similarly, a prospective randomized phase II trial presented its favorable preliminary results for PT when compared to IMRT on glioblastoma. Although there was no significant difference in time to cognitive failure, progression-free survival (PFS), or OS, the PT cohort reported a lower rate of fatigue at 24% compared to 58% for the IMRT population. Furthermore, PT showed a significant reduction in the radiation dose in all structures; as a result, it only showed a mean of 0.35 grade of between 0–3 grade toxicities. On the other hand, IMRT had a range of grade 0–6 toxicities and an average number of 1.15, which is significantly higher in grade toxicity and the number of them [48].

In another randomized phase IIB trial carried out by Lin et al. [49], PT and IMRT were compared again for locally advanced esophageal cancer. In agreement with the previous trial, a total toxicity burden (TTB) was calculated to be 2.3 times higher in the IMRT group than the PT, and similar 3-year PFS rate and OS rates were observed in IMRT and PT to be 44.5% vs. 44.5% and 50.8% vs. 51.2%, respectively. Once again, a lower toxicity is observed in the proton cohort; however, no increase in survival rate has been observed due to the significant difference in toxicity.

Lastly, de González et al. [50] are working on the first large-scale systematic comparison between proton and photon therapy in a variety of pediatric cancers that are commonly treated with radiation from 2007 to 2022. This comparison between the two modalities and the analysis of subsequent cancer risk is an effort to shine light on the clinical practice of pediatric patients, but also hopefully transcend beyond the pediatric cohort, into the lives of everyone else.

Whether it is glioblastoma or advanced esophageal cancer, cohorts showed a better tolerance toward proton therapy, even though the OS rate has consistently shown no significant difference. Such an effect might be explained by the mechanisms and pathways each modality affects. And we must combine their fundamentalities with the clinical data explained above to comprehensively assess which therapy would be more beneficial to cancer cells, but also to patients themselves.

One of the most significant distinctions between proton and photon therapies is the mechanism responsible for proton therapy’s low toxicity—the Bragg peak—which is considered a cornerstone of proton therapy. This unique physical characteristic allows particle therapy to precisely deliver calculated radiation doses to the tumor while effectively sparing surrounding healthy tissues. The advantage lies in proton therapy’s superior ability to preserve normal tissues while providing radiation doses equivalent to, or even greater than, those administered by photon therapy. According to Byun et al. [51], charged particle beams exhibit a distinct depth-dose distribution as they traverse biological tissues towards cancerous lesions; specifically, a steep, localized peak of radiation occurs when particles deposit the majority of their energy in the last few millimeters of their path as they decelerate. This delayed yet concentrated energy deposition enables protons to effectively target abnormal tissues without prematurely releasing radiation energy into healthy structures, thereby maximizing therapeutic efficacy while minimizing toxicity.

In contrast, photons immediately release most of their dose upon their entry and gradually decrease as a function of distance. As a result, there will not only be a dampened effect on cancerous tissues, but also there is a significantly greater toxicity experienced by healthy tissues [50]. However, after the arrival of radiation dosage, both modalities will induce similar biological mechanisms at the cellular level—DNA damage and G2/M arrest, inhibition of cell proliferation, and controlled and quantifiable apoptosis [52].