Integrated management of immunotherapy and radiotherapy for patients with metastatic non-small cell lung cancer: a narrative review of current landscape and future directions

Introduction

The 5-year survival rate among patients with metastatic non-small cell lung cancer (NSCLC) is approximately 9% (1). Although immune checkpoint inhibitors (ICIs) have yielded significant improvements in overall survival (OS) and progression-free survival (PFS), a considerable proportion of patients remain nonresponsive to these therapies (2). Radiotherapy (RT), a traditional standard treatment for NSCLC, has been proven to achieve effective results when combined with ICIs. Research on this topic has mainly concentrated on patients with inoperable locally advanced NSCLC. Studies such as the PACIFIC, LUN-14-179, GEMSTONE-301, and DETERRED trials have demonstrated that the combination of ICIs with concurrent or sequential RT can improve the clinical outcomes of patients with unresectable stage III NSCLC (3-6). However, in metastatic NSCLC, although the combination of RT and immunotherapy has become an area of considerable interest, many concerns regarding the optimal integration of combination therapy remain unresolved. Only a limited number of clinical trials have reported improved outcomes in patients with metastatic NSCLC treated with RT combined with ICIs (Table 1). Several clinical trials investigating the use of RT plus ICIs in patients with metastatic NSCLC are ongoing (Table 2). In this narrative review, we characterize the current status of combined immunotherapy and RT in metastatic NSCLC, and analyze the impact of radiation target sites, RT dose, and treatment sequencing on the efficacy of combination therapy with ICIs. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0018/rc).

Methods

We conducted a systematic search of the PubMed database to identify English-language articles published as of December 2025 using the keywords “non-small cell lung cancer”, “metastasis”, “immunotherapy”, “radiotherapy”, and their synonyms. Relevant information from clinical studies was also retrieved from ClinicalTrials.gov. Two authors (Xinquan Liang and F.L.) independently screened the titles and abstracts of all identified records based on predefined inclusion and exclusion criteria. English-language articles—including original research, reviews, and clinical trials—focusing on metastatic NSCLC were included, whereas case reports, editorials, letters to the editor, and conference abstracts were excluded. The full texts of potentially eligible studies were subsequently obtained and independently assessed by the same two reviewers. Any discrepancies in study inclusion were resolved through consensus discussion. Furthermore, reference lists of the included articles were manually screened to identify additional relevant studies and supplement the evidence base. All included studies are cited in the References section, and the complete search strategy is provided in Table 3.

Mechanisms of ICI resistance

The effectiveness of ICIs relies on a strong anticancer immune response (2). Tumors can become resistant by using adaptive mechanisms to evade immune detection. These mechanisms have the potential to disrupt various phases of the cancer immunity cycle (CIC), thereby reducing the overall impact of ICI therapy (Figure 1). These mechanisms encompass: the absence of programmed death-ligand 1 (PD-L1) expression; insufficient tumor antigenicity; defects in antigen presentation—most notably mutations in β-2-microglobulin (B2M); escape mutations that disrupt the interferon gamma (IFN-γ) signaling cascade; dysregulation of immunosuppressive pathways—including MAPK, PI3K, WNT/β-catenin, and IFN-γ signaling—that collectively impair immune cell infiltration and effector function; and downregulation or loss of major histocompatibility complex (MHC) class I molecule expression (7,8). Additionally, resistance may be driven by the tumor microenvironment (TME), which actively suppresses anticancer immune responses, largely through the production of immunosuppressive cytokines and the recruitment of inhibitory cell populations. Several key processes contribute to this phenomenon. T cells exhibit impaired infiltration into the TME, whereas immunosuppressive cell populations—including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2-polarized tumor-associated macrophages (TAMs)—expand significantly; concurrently, cancer cells and cancer-associated fibroblasts secrete immunosuppressive molecules (9). Furthermore, the increased expression of alternative immune checkpoints, including programmed death-1 (PD-1) homolog (PD-1H) (VISTA), LAG3, and TIM3, during the development of acquired resistance may reflect terminal T-cell exhaustion and permanent loss of functional capacity (10). Understanding how resistance develops is key to creating novel treatments for this severe clinical issues.

Figure 1 Mechanisms of immune-mediated resistance to ICIs. This figure was created using FigDraw. (A) Lack of PD-L1 expression. (B) Neoantigen depletion. (C) Defects in antigen presentation. (D) Loss of IFN-γ sensitivity. (E) Tumor-mediated immune suppression or exclusion. (F) Upregulation of immune inhibitory receptors. (G) Recruitment of immunosuppressive cells. (H) Metabolic and inflammatory mediators. (I) T-cell exclusion. ICIs, immune checkpoint inhibitors; IFN-γ, interferon gamma; IFNGR, interferon-γ receptor; JAK, Janus kinase; LAG-3, lymphocyte-activation gene 3; MHC, major histocompatibility complex; PD-1, programmed death 1; PD-1H, PD-1 homolog; PD-L1, programmed death ligand 1; TCR, T-cell receptor; TIGIT, T cell immunoglobulin and ITIM domain; TIM-3, T-cell immunoglobulin and mucin domain-containing molecule 3; VISTA, V domain immunoglobulin suppressor of T-cell activation.

Impact of RT on antitumor immunity

Traditionally, the clinical efficacy of RT has been viewed as a localized effect, with the promotion of DNA damage and direct killing of tumor cells (11). However, a growing body of evidence suggests that RT and the immune system interact, with recent findings indicating that RT can boost both local and systemic immunity, enhancing antitumor activity. As a result, its role is shifting from merely inducing tumor cell death to actively modulating immune responses and altering the TME.

Dual role of RT in immune response

The immunoregulation effects of RT—whether enhancing or inhibiting—can be explained through multiple biological pathways (Figure 2).

Figure 2 Radiotherapy elicits both antitumor immune responses and immunosuppressive effects. This figure was created using FigDraw. When RT targets cancer cells, it increases MHC class I expression and exposes calreticulin on the cell surface. Irradiation leads to dsDNA formation, the release of tumor-specific peptides, and activation of the cGAS/STING/IFN-I pathway, which enhance antitumor immunity. The transcription and secretion of type I IFN stimulate receptors on tumor cells, DCs, and T cells, remodeling the inflammatory microenvironment. RT induces immunogenic cell death, resulting in the release of DAMPs and nearby TAAs. DAMPs promote transcription related to antigen presentation machinery and support APC maturation. The release of TAAs facilitates priming and activation of effector T cells for antitumor responses. DCs recognize these TAAs and transport them to lymph nodes where they present them to naïve CD8⁺ T cells via MHC I along with CD80/86 and CD28 co-stimulatory receptors. Activated cytotoxic T cells then enter circulation, migrating toward distant metastases and returning to irradiated tumors for disease elimination. RT stimulates both tumor and stromal cells to produce chemokines such as CXCL9, CXCL10, CXCL11, and CXCL16; these chemokines lead to infiltration by DCs, macrophages, and T cells, further promoting an inflammatory tumor microenvironment. Repeated irradiation induces chronic activation of cGAS-STING signaling that promotes immunosuppression. Type I IFN enhances PD-L1 expression on APCs, inhibiting T-cell function. RT also triggers IDO release which fosters an inhibitory immune microenvironment at the tumor site while stimulating MDSC activity alongside Treg function; this promotes secretion of TGF-β and IL-10, thereby suppressing T-cell activation. Additionally, RT initiates the production of chemokines such as CCL2 and CCL5 in the tumor microenvironment; increased levels drive infiltration by Tregs, macrophages, and MDSCs. APC, antigen-presenting cell; ATP, adenosine triphosphate; cGAS, cyclic GMP-AMP synthase; DAMP, damage-associated molecular pattern; DC, dendritic cells; DSB, double-strand break; dsDNA, double-strand DNA; HMGB1, high mobility group box 1 protein; IDO, indoleamine 2,3-dioxygenase; IFN-I, interferon I; IFN-R, interferon receptor; IL-10, interleukin 10; MDSC, myeloid-derived suppressor cells; MHC, major histocompatibility complex; mtDNA, mitochondrial DNA; PD-1, programmed death 1; PD-L1, programmed death-ligand 1; RT, radiotherapy; STING, stimulator of interferon genes; TAA, tumor-associated antigen; TCR, T-cell receptor; TGF-β, transforming growth factor beta; TLR, toll-like receptor; Treg, regulatory T cell.

Immune activation effects

The main molecular mechanisms that positively modulate both adaptive and innate antitumor responses through RT are as follows (12). Radiation-induced immunogenic cell death (ICD) unleashes a cascade of immune activation by triggering the release of tumor-specific antigens, stimulating T-cell responsiveness, and orchestrating their strategic infiltration into the TME—ultimately galvanizing a unified and robust antitumor immune defense (13,14). This process contributes to a coordinated antitumor immune response by improving antigen presentation, T-cell activation, and their migration to the TME. Damage-associated molecular patterns (DAMPs) function as key mediators in RT-induced CD, mediating the translocation of calreticulin and heat shock proteins to the cell surface, the extracellular release of high mobility group box 1 (HMGB1), and the secretion of adenosine triphosphate (ATP) (15,16). Elevated DAMP signaling enhances the expression of tumor-associated antigens (TAAs), particularly neoantigens generated through radiation-induced mutational events. In addition to promoting inflammatory cytokine release, DAMPs also enhance the effector functions of activated CD8⁺ T lymphocytes (17). A pathway receiving increasing attention is the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis, which serves as a critical signaling route that upon activation, induces the expression of type I IFNs. This process plays a key role in dendritic cell (DC) activation and the priming of effector T cells (18,19). Consequently, it initiates the activation of tumor-specific T lymphocytes, significantly increasing their numbers, enhancing T-lymphocyte activation, and amplifying the tumor-specific immune response (20-22). Radiation promotes the release of double-stranded DNA (dsDNA) from the nucleus and leads to the exposure of mitochondrial DNA (mtDNA) in the cytoplasm (23). Both dsDNA and mtDNA function as potent activators of the cGAS-STING pathway, thereby inducing the transcriptional upregulation of type I IFN. The activation of the cGAS/STING pathway by RT thus elicits a type I IFN response (12). RT has the capacity to alter the phenotype of tumor cells, thereby significantly enhancing their immunogenicity and increasing antigen visibility. Emerging evidence indicates that RT enhances the host immune system’s recognition and elimination of tumor cells. This effect is mediated by the upregulation of MHC class I molecule expression on tumor cell surfaces, which enhances the infiltration of CD8⁺ and CD4⁺ T lymphocytes. As a result, these cells can effectively recognize TAAs, leading to the initiation of antitumor immune responses (24,25). MHC class I expression increases in a dose-dependent manner following exposure to RT (26).

Radiation fractures DNA through the ATM-ATR-Chk1 axis, immediately raising PD-L1 expression and later amplifies the same ligand indirectly via IFN-γ and other inflammatory signals (27,28). It also primes intrinsic apoptosis and upregulates Fas on tumor cells. Fas regulates apoptosis: its expression determines tumor cell survival or death. When cytotoxic T lymphocytes recognize tumor cells, FasL binds to Fas, triggering apoptosis. Thus, radiation enhances tumor cell sensitivity to immune killing by upregulating Fas (14). In parallel, irradiated tumor and stromal cells release a spectrum of inflammatory mediators that remodel the microenvironment (29). Proinflammatory cytokines and chemokines recruit and activate DCs, macrophages, and T lymphocytes (27). Within the myeloid compartment, RT induces the repolarization of TAMs. This process shifts TAMs from an immunosuppressive M2 phenotype toward an immunostimulatory M1 phenotype that expresses inducible nitric oxide synthase (iNOS). These reprogrammed TAMs subsequently secrete Th1-polarizing chemokines and cytokines, such as CXCL9, CXCL10, and IL-12. The resulting chemokine gradient facilitates the recruitment of CD8⁺ cytotoxic T lymphocytes and CD4⁺ T helper 1 (Th1) cells into the TME, ultimately amplifying the antitumor immune response (30,31).

Immunosuppressive effects

RT can exert several immunosuppressive effects (32), for example, inducing immunosuppression and lymphopenia. The immunogenic dose of RT results in the accumulation of dsDNA in cancer cells, activating the cGA/STING signaling pathway to promote type I IFN gene transcription (20). However, IFN signaling also exerts a detrimental impact that contributes to therapeutic resistance. Repeated irradiation of tumor cells gives rise to chronic type I IFN and the expression of IFN-stimulated genes, mediating radiation resistance and metastatic dissemination through multiple inhibitory pathways (33,34). IFN-γ and type I IFN promote PD-L1 upregulation in tumor cells, leading to T-cell exhaustion and reduced antitumor immunity (35,36). Both cytokines also induce the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) (37), which enhances T-cell exhaustion and upregulates inhibitory receptors and their ligands (38).

Moreover, activated STING signaling enhances the mobilization of Tregs and MDSCs, thus eliminating tumor immunogenicity (39,40). Local RT increases the secretion of CCL2 and CCL5, which attract Tregs and monocytes (41,42). The recruited monocytes activate Tregs in a TNF-α-dependent manner, reducing the efficacy of RT and mediating tumor immune resistance (41). Tregs secrete inhibitory cytokines such as interleukin (IL)-10 and transforming growth factor beta (TGF-β), further strengthening the immunosuppressive effects of MDSCs and suppressing the function of effector T cells (43,44).

RT causes lymphopenia largely by irradiating lymphatic organs. To reduce local and regional recurrence, radiation fields often include the primary tumor’s draining lymph nodes. However, naïve T cells are highly radiosensitive, and even low-dose exposure to lymphoid tissues can induce rapid p53-mediated apoptosis (45,46), leading to a reduced lymphocyte count, increased T-cell apoptosis, and poorer survival (31). Elective nodal irradiation, a conventional approach, not only suppresses adaptive immunity but also weakens the synergy between RT and immune checkpoint blockade (47,48). Preclinical studies indicate that nodal irradiation compromises local tumor control and reduces effector T-cell infiltration into tumors (48), effects not fully reversible by ICIs alone (49). Preserving lymphocyte function is therefore essential. Smaller, more targeted radiation volumes—which avoid damage to draining lymphatics—better preserve antitumor immunity and may improve survival when combined with ICIs.

Dose and fractionation

Given RT’s dual immune-activating and immune-suppressive effects, optimal dose and fractionation should be carefully considered. Preclinical studies demonstrate that higher-dose RT triggers robust intracellular stress, characterized by reactive oxygen species (ROS)-mediated DNA damage. This damage is a key driver of ICD (50). Consequently, higher-dose RT enhances the infiltration of tumor-specific CD8⁺ T cells. It also upregulates critical molecules such as Fas and intercellular adhesion molecule (ICAM), and promotes the expression of tumor-associated peptides (26,51,52). It also promotes immunogenic cell surface markers—such as ICAM-1, MHC class I, and Fas—in a dose-dependent manner (1–20 Gy), with higher doses linked to greater expression (26,53,54). Additionally, RT stimulates chemokine release and vascular changes, promoting immune cell recruitment to irradiated tumors (55). Doses above 15 Gy damage blood vessels by impairing endothelial cell viability, causing tumor cell starvation and apoptosis (56). These changes can worsen hypoxia in the TME and promote radioresistance (57). Among monotherapies, single doses of 7–12 Gy show stronger immune-modulatory effects than do high-to-ablative doses (≥15 Gy) (52). Stereotactic body radiotherapy (SBRT) is the most common high-dose approach, and a regimen of 8–10 Gy per fraction in one or two fractions is now widely considered optimal for triggering robust antitumor immunity (58).

Low-dose radiotherapy (LDRT; 0.5–2 Gy per fraction and ≤20 Gy total) is nonablative (59-61), and while it does not control tumor growth, it reshapes immunity. LDRT curbs nitric oxide and IL-1β expression, while raising IL-10 and TGF-β expression, thus shifting macrophages toward an anti-inflammatory profile (62,63). Minimal cell death after LDRT results from efficient DNA repair in tumor cells and tumor-associated fibroblasts. LDRT preserves tumor vasculature and promotes angiogenesis via circulating endothelial or bone marrow-derived progenitor cells (64). This vascular normalization improves oxygenation and allows antigen-specific T cells to enter the tumor (65,66). Because leukocytes are radiosensitive, LDRT depletes suppressive subsets (67) and, by upregulating endothelial ICAM-1, boosts white-cell extravasation and pushes macrophages to an M1 phenotype (66,68).

Hypofractionated regimens are more immunogenic than are single ablative doses, yet direct comparisons of their local and systemic immune effects remain limited. In vitro, fractionated radiation (5× 2 Gy or 3× 5 Gy) induces stronger human DC maturation than does a single 15 Gy dose (69), likely due to differences in cell death pathways. Clinically, both conventional RT (1.8–2.0 Gy per fraction) and hypofractionated regimens (e.g., 3× 9.5 Gy or 5× 6 Gy) can activate antitumor immunity and enhance the efficacy of concomitant systemic immunotherapy (70). Notably, the majority of reported abscopal responses have been associated with hypofractionated approaches (71). Nevertheless, prospective comparative trials are still required to systematically evaluate different dose and fractionation strategies, thereby optimizing combination regimens of RT and immunotherapy.

Combination of RT and ICIs in metastatic NSCLC

RT and immunotherapy can synergize, forming an established oncologic strategy that has underpinned a number of clinical trials. Recently, the research on RT combined with ICIs for treating metastatic NSCLC has intensified, with a growing body of evidence supporting their synergistic benefit in improving patient outcomes.

Thoracic RT and ICIs

Advances in thoracic RT in combination with ICIs

Historically, RT was primarily used for palliative symptom alleviation in patients with metastatic NSCLC. In the era of immunotherapy, the synergistic interaction between thoracic RT and ICIs underscores the substantial clinical importance of thoracic RT for patients with metastatic NSCLC.

A number of studies have reported that combining thoracic RT with immunotherapy improves survival in patients with advanced NSCLC. One retrospective study examined 302 patients, of whom 54.3% (164/302) received ICIs plus thoracic RT (thoracic RT + ICI group) and 45.7% (138/302) received ICIs alone (ICI-only group). The median OS was significantly longer in the thoracic RT + ICI group (34.7 months) than in the ICI-only group (27.1 months; P=0.02). The 24- and 36-month survival rates were also higher in the thoracic RT + ICI group (63.7% and 49.0%, respectively) than in the ICI-only group (55.1% and 16.2%, respectively) (72). A study by Kharouta et al. found that the incorporation of thoracic RT improves short-term OS in patients with metastatic NSCLC, with a higher biologically equivalent dose (BED) value improving survival. The 2-year OS rate was 27.7% for patients receiving thoracic RT plus immunotherapy, while it was 22.2% among those treated with immunotherapy alone (P=0.004). On multivariable analysis, thoracic RT was significantly associated with OS after adjusting for age, race, comorbidity score, sex, and median income [hazard ratio (HR) 0.87, 95% confidence interval (CI): 0.80–0.94; P=0.0003]. Among patients receiving BED₁₀ >39 Gy (equivalent to 30 Gy in 10 fractions), the 2-year OS rose from 18.1% to 37.0% (P<0.0001). These findings suggest that adding thoracic RT improves short-term OS in patients with metastatic NSCLC and that a higher BED₁₀ is associated with better survival (73). Qin et al. assessed combining thoracic RT with first-line immunotherapy and chemotherapy for treating patients with advanced lung squamous cell carcinoma (LUSC). Among 34 patients with pulmonary lesions, those receiving thoracic RT were matched 1:1 with controls. Thoracic RT significantly improved median PFS (14.8 vs. 7.4 months; HR 0.36, 95% CI: 0.163–0.507; P<0.001), and the median OS was also higher (19.7 vs. 12.8 months; HR 0.50, 95% CI: 0.235–0.865; P=0.02). The recurrence rate was lower with thoracic RT (8.8%) than without it (58.8%) (P<0.05). Among patients receiving RT, conventional RT (60 Gy/2 Gy/30 fractions; n=19) achieved a local control rate of 89.5%, hypofractionated RT (60 Gy/4 Gy/15 fractions; n=11) achieved 81.8%, and the 50 Gy/5 Gy/10 fraction regimen (n=4) achieved 75%. These results indicate that the addition of thoracic RT improves outcomes in patients with advanced LUSC when combined with immunotherapy and chemotherapy (74). The phase I SICI trial primarily evaluated the safety and tolerability of SBRT to the primary tumor in combination with durvalumab, with or without tremelimumab, in 15 patients with metastatic NSCLC. Cohort 1 (n=3) received durvalumab alone, cohort 2 (n=6) received tremelimumab plus durvalumab followed by durvalumab monotherapy, and cohort 3 (n=6) received the same agents in reverse sequence. All patients started immunotherapy 4 days before SBRT. The median PFS was 2 months (range, 1–20 months), the median OS was 10 months (range, 1 month to not reached), the median duration of clinical benefit was 39 weeks (range, 25–90 weeks), the objective response rate (ORR) was 13%, and the disease control rate was 20% at 6 months and 6% at 12 months. The study concluded that combining SBRT to the primary tumor with dual immunotherapy is safe and feasible in patients with metastatic NSCLC (75). Another study evaluated the efficacy and safety of RT combined with antiangiogenic therapy, ICIs, and chemotherapy in patients with advanced NSCLC. Seventy-four patients were divided into two groups (A and B) based on whether they received RT. Survival analysis showed that adding RT significantly improved OS (HR 0.51, 95% CI: 0.283–0.919; P=0.02), with improved PFS. However, RT was associated with increased risks of radiation-related pneumonitis (P<0.001), pneumonia (P=0.04), and thrombocytopenia (P<0.001), all of which negatively affected prognosis. Sequential RT after quadruple therapy may prolong survival in patients with advanced NSCLC, but treatment-related toxicities require careful monitoring (76).

Multiple studies have demonstrated that combining RT and granulocyte-macrophage colony-stimulating factor (GM-CSF) effectively activates the innate immune system (77,78). The SWORD trial (NCT04106180), a prospective, multicenter, phase II study conducted in patients with metastatic NSCLC, investigated the safety and therapeutic outcomes of using SBRT together with GM-CSF and PD-1/PD-L1 inhibitors as a second-line regimen. Over 70% of patients received thoracic SBRT. Among the 49 evaluable patients, 18 (36.7%; 90% CI: 25.3–49.5%) had an objective response. The out-of-field (abscopal) response rate (ASR) was 30.6% (95% CI: 18.3–45.4%). The median PFS was 5.9 months (95% CI: 2.5–9.3), and the median OS was 18.4 months (95% CI: 9.7–27.1). Treatment-related adverse events (TRAEs) occurred in 44 patients (86.3%), including grade 3 in 6 (11.8%), and no grade 4 or 5 TRAEs were reported. The triple therapy was well tolerated and showed promising efficacy (79).

Optimal timing of thoracic RT and ICIs

The optimal timing of thoracic RT in patients with metastatic NSCLC remains unclear. Several studies have examined how prior RT affects outcomes when given before ICIs. In the PEMBRO-RT trial, Theelen et al. assessed SBRT to a single tumor site before pembrolizumab in 92 patients with metastatic NSCLC; ultimately, 76 patients were randomized to a control group (n=40) or an experimental group (n=36). Pembrolizumab (200 mg every 3 weeks) was administered either alone (control arm) or after RT (3×8 Gy) (experimental arm). SBRT targeted lung lesions or lymph node metastases. The study demonstrated that median PFS and median OS were 6.6 months (vs. 1.9) and 15.9 months (vs. 7.6), respectively, in the SBRT plus pembrolizumab group, significantly longer than in patients receiving pembrolizumab alone. The ORR at 12 weeks was 18% in the control arm vs 36%in the experimental arm (P=0.07). Although the primary endpoints were not significant, improvement was observed in the PD-L1-negative patients, and SBRT before pembrolizumab was well tolerated (80). Other studies have evaluated concurrent use of RT with ICIs. A phase I/II trial [The University of Texas MD Anderson Cancer Center (MDACC); NCT02444741] examined pembrolizumab alone or with concurrent RT (SBRT: 50 Gy/4 fractions; conventional RT: 45 Gy/15 fractions) in 100 patients, with most receiving thoracic RT. No significant differences were found in ORR between the combination and monotherapy groups (22.0% vs. 25.0%; P=0.99) or in the median PFS (9.1 vs. 5.1 months; P=0.52). However, among combined arms, out-of-field ORR was higher with SBRT (38%) than with conventional RT (10%; P=0.11), with a median PFS of 20.8 and 6.8 months, respectively (P=0.03). In patients with low PD-L1 expression, the median PFS was 4.6 months with pembrolizumab alone and 20.8 months with RT combination (P=0.004). These results suggest concurrent SBRT may be more effective than conventional RT when combined with immunotherapy in patients with metastatic NSCLC (81).

Brain RT and ICIs

Approximately half of patients with NSCLC develop brain metastases (BMs), and the median survival of these patients is about 7 months (82-84). Chemotherapy and first-generation targeted drugs exert scant intracranial activity due to the blood-brain barrier (BBB) blocking delivery (83,85,86). Irradiation can modify BBB function, allowing immune cells and ICIs to enter the brain (87,88). Studies show that stereotactic radiotherapy (SRT) increases BBB permeability more than conventional RT, potentially enhancing the entry of systemic agents and immune cells into the central nervous system (89,90). Higher SRT doses per fraction may further amplify this effect (91).

Advances in RT for BMs and ICIs

Whole-brain RT and SRT are the primary local treatments for patients with NSCLC and BMs. Although the role of immunotherapy combined with SRT has not been fully defined, evidence shows it is effective against intracranial disease (92,93). Therefore, the addition of immunotherapy for these patients has been recommended, especially those with signs of intracranial hypertension or requiring palliative RT for symptomatic disease (94). A multicenter phase II study, the C-Brain trial (NCT04291092), was conducted to evaluate the efficacy and safety of combining brain RT with camrelizumab and platinum-based chemotherapy as first-line treatment in patients with NSCLC and BMs. A total of 65 treatment-naïve adult patients with symptomatic BMs and no known EGFR, ALK, or ROS1 alterations were enrolled. With a median follow-up of 14.1 months, the study reported a 6-month PFS rate of 71.7% (95% CI: 58.9–81.1%), a median PFS of 10.7 months (95% CI: 7.5–15.7), and a median OS of 20.9 months (95% CI: 13.8–27.7). Grade 3 neurological toxicity occurred in 5% of patients, and radiation necrosis (all grade 1 or 2) was observed in another 5%. The regimen showed promising efficacy and manageable toxicity (95). A pooled analysis (96) evaluated the efficacy of combining RT, immunotherapy, and platinum-doublet chemotherapy in patients with NSCLC with BM. Data from three open-label, randomized phase III trials (IMpower130, IMpower131, and IMpower150) were retrospectively analyzed. Patients who received RT plus immunotherapy and chemotherapy were compared with those receiving immunotherapy and chemotherapy alone. After PSM, the combination group had significantly longer median OS than did the noncombination group (18.7 vs. 11.8 months; HR 0.49, 95% CI: 0.29–0.83; P=0.007) and PFS (7.1 vs. 5.75 months; HR 0.54, 95% CI: 0.37–0.78; P=0.02). The findings indicated that adding RT prolongs both OS and PFS in patients with NSCLC and BMs (96). A retrospective, multicenter study evaluated the efficacy and safety of combining SRT, ICIs, and chemotherapy in driver gene-negative NSCLC patients with brain oligometastases. In the propensity score-matched cohort (n=207), the SRT + ICI + chemotherapy group, as compared to the SRT + chemotherapy and ICI + chemotherapy groups, had a significantly higher intracranial ORR (55.2% vs. 32.9%/49.4%; P=0.01), a longer median OS (24.7 vs. 14.7/17.8 months; P=0.03), and an improved intracranial PFS (17.0 vs. 7.8/13.0 months; P=0.001). No increase in central nervous system or immune-related adverse events was observed. Overall, concurrent SRT, ICIs, and chemotherapy improved survival and intracranial control in patients with NSCLC and brain oligometastases without increasing toxicity (97).

Several studies have reported that the combination of immunotherapy and brain RT does not significantly prolong median OS in patients. A multicenter retrospective study assessed the safety and efficacy of first-line immunotherapy in 138 patients with NSCLC and BMs. Those receiving ICIs plus brain RT tend to have a longer OS compared to those treated with ICIs alone, but the difference was not significant (P=0.20). Among 82 patients with available data, the independent ORR was 49.1% (95% CI: 35–63%) with ICIs alone and 75.9% (95% CI: 56–90%) with ICIs plus RT (98). Guo et al. analyzed data from seven prospective trials to assess the effect of prior cranial RT on atezolizumab outcomes in patients with NSCLC and BMs. Patients with irradiated BMs (n=280) tended to have a longer OS than did those with nonirradiated BMs (n=28) (median OS: 19.2 vs. 10.6 months; P=0.09), suggesting synergy between cranial RT and PD-1/PD-L1 inhibitors (99).

RT combined with immunotherapy may improve clinical outcomes in patients with NSCLC and BMs. Ongoing phase III trials, including USZ-STRIKE (100), will provide definitive evidence for clinical guidance.

Optimal timing of RT and ICIs for BMs

In NSCLC treatment, timing the combination of RT and ICIs in patients with BMs is crucial. Recent studies have consistently reported improved outcomes with upfront SRT combined with ICIs compared to ICI monotherapy. For example, a multicenter retrospective analysis included 128 patients with metastatic NSCLC and asymptomatic BMs across two cohorts: 58 received upfront SRT and 69 did not. The median intracranial PFS was significantly longer with upfront SRT than without it (12.6 vs. 8.2 months; HR 0.62, 95% CI: 0.41–0.95; P=0.03). No significant difference in median OS was observed (22.8 vs. 21.7 months, P=0.4). Upfront SRT was associated with improved intracranial PFS and was well tolerated, but rates of symptomatic brain progression and OS were similar between the groups (101). A retrospective multi-institutional study by Guo et al. enrolled 110 patients with NSCLC and BMs. Patients were categorized based on whether they received upfront cranial radiotherapy (uCRT) at any time between the initiation of ICIs and the first subsequent progression. Patients receiving uCRT combined with ICIs had a longer median OS than did those not receiving uCRT (25.4 vs. 14.6 months; HR 0.52, 95% CI: 0.29–0.91; P=0.04); the survival benefit was greater in patients with 1–4 BMs (25.4 vs. 17.0 months; HR 0.42, 95% CI: 0.22–0.81; P=0.02), and uCRT was independently associated with improved OS (102).

Several pivotal studies [e.g., (91,97,103)] have established that concurrent RT and ICIs confer superior antitumor immunity and survival outcomes compared to sequential scheduling. In a retrospective, multicenter study of patients with brain oligometastases from driver gene-negative NSCLC, concurrent therapy with SRT, ICIs, and chemotherapy (within 2- or 4-week intervals) was associated with significantly better outcomes than was sequential therapy, including a longer OS (31.6 vs. 17.2–17.7 months), independent PFS, as well as a higher independent ORR (66.1%/67.2% vs. 39.1%/35.6%) and independent disease control rate (97). A retrospective study analyzed patients with NSCLC treated with brain RT and ICIs to compare the survival outcomes between concurrent and consolidation ICI administration. The cohort included 54 patients receiving concurrent ICIs with RT and 62 receiving RT followed by consolidation ICIs. The ORRs were similar between groups; the median PFS was significantly longer in the concurrent group (9.56 vs. 8.15 months; P=0.04); and the median OS was also higher (22.08 vs. 13.24 months, P=0.009). In patients with NSCLC and BMs, the regimen of concurrent ICIs combined with RT was associated with significant clinical benefit as compared to consolidation ICI after RT (103). Another multicenter retrospective study included 100 patients who received SRT plus immunotherapy and 50 who received SRT alone. The combination significantly improved intracranial local PFS (iLPFS) compared to SRT alone (89.5% vs. 83.9%, adjusted P=0.007). When the interval between SRT and immunotherapy was ≤7 days (n=90), it was associated with better OS as compared to intervals >7 days (n=10; propensity score-adjusted P=0.008). The combination also showed a favorable safety profile (91).

Yu et al. found that nondelayed RT—concurrent or upfront—combined with immediate PD-1/PD-L1 inhibitors—was linked to better survival outcomes than was delayed RT. The study included 73 patients, with a median follow-up of 13.9 months. Among them, those who received delayed RT had significantly shorter iLPFS (P=0.003), intracranial distant PFS (iDPFS) (P=0.02), and OS (P<0.001). A meta-analysis incorporating four studies and 254 patients was conducted. When concurrent RT was compared with delayed RT, the HRs were 0.44 for iDPFS (P=0.03) and 0.41 for OS (P<0.01). For the comparison of upfront RT with delayed RT, the HRs were 0.21 for iDPFS (P<0.01) and 0.32 for OS (P<0.01). These findings align with the conclusion that delayed RT is associated with worse iDPFS and OS. A 2-week interval is recommended to define nondelayed RT, as shorter intervals are linked to better local control and improved brain response (104). Although the available data indicate that the combination of cranial RT and ICIs provides substantial survival benefits for patients with NSCLC and BMs, there remains no consensus on the optimal RT dose or treatment schedule. Early interventional RT in the context of immunotherapy may be considered. However, clinical decisions should be guided by the size and number of metastases in accordance with established brain RT principles.

Multisite RT and ICIs

Oligometastatic disease is defined as 1 to 5 metastatic lesions—a definition formally endorsed by recent consensus guidelines from the European Society for Radiotherapy and Oncology and the American Society for Radiation Oncology (105). In NSCLC, oligometastatic disease constitutes a biologically distinct clinical state situated between locally advanced and widely disseminated metastatic disease. Early efforts to reduce toxicity in patients with metastatic NSCLC limited radiation to a single lesion, yet emerging data suggest that such focal treatment fails to prime tumor-infiltrating lymphocytes at distant sites (106,107). Irradiating several deposits can broaden exposure to TAAs, thereby amplifying systemic immunity, lowering overall tumor burden, and potentiating subsequent immune-checkpoint inhibition (108). As a result, current protocols increasingly support multisite irradiation, and ongoing trials combining this approach with immunotherapy are focusing on patients with oligometastatic disease.

Oligometastatic disease is associated with a better prognosis than is extensive metastasis, and combining multisite RT with ICIs may improve efficacy. A single-arm phase II trial (NCT02316002) enrolled 45 patients with oligometastatic NSCLC who received local ablative therapy (LAT), such as RT or surgery, to treat all known metastases and subsequent pembrolizumab administration. The median PFS from LAT initiation was 19.1 months, significantly higher than the historical median of 6.6 months (P=0.005), while PFS from pembrolizumab initiation was 18.7 months. The 2-year OS rate was 90.9%, and the 2-year OS rate was 77.5%. The addition of pembrolizumab after LAT improved PFS without negatively affecting quality of life (109). In the SABRcure trial, durvalumab and platinum-doublet chemotherapy were delivered for four cycles, followed by RT to every lesion and subsequent durvalumab until progression, intolerance, or for a maximum of 24 months. Of the 35 patients with EGFR/ALK-wild-type oligometastatic NSCLC, 28 (80%) completed RT, and 23 (65.7%) completed SBRT. The median PFS was 10.4 months, the 1-year OS rate was 73.6 %, and the ORR was 71.9%. RT prolonged the median PFS to 18.7 months, and SBRT prolonged it to 24.3 months (110). Other groups are now testing SBRT administered to all metastatic sites combined with dual immune-checkpoint blockade in the same setting. In a phase Ib trial (NCT03275597) by Bassetti et al., all lesions were treated with SBRT (30–50 Gy in 5 fractions), which was followed by tremelimumab and durvalumab 7 days later for four cycles and then maintenance durvalumab until progression or toxicity. Seventeen patients were enrolled. The median PFS was 42 months, and the median OS was not reached at the time of analysis. Compared with historical data on immunotherapy alone, the combination of SBRT with dual-checkpoint immunotherapy did not increase toxicity. Although the study was not primarily designed to assess efficacy, the durable PFS and OS suggested a potential benefit over single-modality treatments (111). A multicenter, phase II, single-arm study enrolled 35 patients, of whom 23 (65.7%) received stereotactic ablative RT (SABR). The median PFS was 24.3 months [95% CI: 7.6– not estimable (NE)] with SABR and 3.1 months (95% CI: 1.4–4.7) without SABR (HR 0.2, 95% CI: 0.09–0.5; P<0.001). In patients with oligometastatic NSCLC, the combination of durvalumab, chemotherapy, and SABR was found to be effective and well tolerated (112).

Other research has investigated multisite RT combined with immunotherapy in treating patients with widespread metastatic NSCLC. Given the promising but debated effects of SBRT combined with ICIs, as well as the TME-enhancing potential of LDRT, Zhou et al. conducted a clinical study (NCT03812549) to evaluate the efficacy and safety of combining LDRT and SBRT with sintilimab in treatment-naïve patients with PD-L1-positive metastatic NSCLC. Patients with small lesions received SBRT (30 Gy/3 fractions), while those with large lesions received concurrent LDRT (2 Gy/1 fractions, 4 Gy/2 fractions, or 10 Gy/5 fractions), followed by sintilimab. The median follow-up duration was 15.6 months. Among the 28 evaluable patients, the ORR was 60.7%, including a confirmed ORR of 57.1%; the median PFS was 8.6 months; and the median OS was not reached. Exploratory analyses revealed that both expanded and new T-cell receptor clonotypes were associated with improved PFS. These findings suggest that combining SBRT, LDRT, and sintilimab is safe and clinically promising for patients with PD-L1-positive, driver gene-negative metastatic NSCLC (113). The randomized phase I COSINR trial (NCT03223155) by Bestvina et al. compared concurrent with sequential multisite SBRT with nivolumab and ipilimumab in patients with treatment-naïve metastatic NSCLC. Up to four metastatic sites were treated with SBRT at 45–50 Gy in 3–5 fractions. Of the 37 patients included, 18 received concurrent therapy and 19 received sequential therapy. The distribution of response rates was as follows: 5.4% (2 out of 37) achieved a complete response, 40.5% (15 out of 37) had a partial response, 16.2% (6 out of 37) experienced stable disease, and 37.8% (14 out of 37) had progressive disease. The median PFS was 7.9 months in the concurrent group and 4.7 months in the sequential group, with no statistically significant difference (P=0.43). The study showed that concurrent administration is not more toxic than sequential therapy and that multisite SBRT is generally well tolerated (114).

Evidence on the survival benefit of multisite SBRT or total-site irradiation combined with ICIs for patients with NSCLC and extensive metastases (≥5 sites) remains limited. Delivering SBRT to four or more lesions is challenging due to a daily limit of approximately three isocenters (115). However, one review suggested that better outcomes may be achieved by administering SBRT to all lesions over multiple cycles—targeting one or two per cycle—rather than in a single cycle (116). This has sparked interest in a “pulsing” SBRT approach to enhance and sustain antitumor immunity, potentially improving survival. This pulsing strategy or addition of LDRT may further boost immune activation. Prospective trials are needed to generate robust evidence and establish clear guidelines.

Fractionation patterns of RT and ICIs

The optimal RT fractionation for combination with immunotherapy remains unclear. In the phase II PEMBRO-RT trial (NCT02492568), 8 Gy × 3 SBRT delivered immediately before pembrolizumab increased ORR and prolonged PFS and OS (80).

A further randomized phase II trial evaluated the efficacy of durvalumab plus tremelimumab alone or in combination with LDRT (0.5 Gy twice daily for 2 days during the first four cycles) or hypofractionated RT (24 Gy in 3 fractions of 8 Gy each during the first cycle). The study included 78 patients (26 per group) with primary or acquired immune-resistant metastatic NSCLC. After a median follow-up of 12.4 months, no significant differences in ORR were observed between the durvalumab-tremelimumab alone group and either the LDRT group or the hypofractionated RT group (117).

According to the COSINR study, SBRT doses for the first-line treatment of patients with metastatic NSCLC in combination with immunotherapy are recommended as follows: 30 Gy in 3 fractions for osseous, spinal, or paraspinal metastases; 45 Gy in 3 fractions for peripheral lung, liver, abdominal, and pelvic metastases; and 50 Gy in 5 fractions for central lung and mediastinal, cervical, or axillary lymph nodes (114). Research indicates that SBRT combined with ICIs can be delivered at doses ranging from 30 to 50 Gy over 3 to 5 fractions while maintaining acceptable toxicity levels (118). Most clinical trials administer RT on alternate days rather than consecutive days, based on the hypothesis that lymphocytes require approximately 48 hours to recover (119). The ideal dose and fractionation should effectively prime antitumor immunity while minimizing adverse effects. Given the limited available evidence, distinct optimal dose and fractionation schedules may exist for patients with different tumor characteristics and immune profiles.

Conclusions

Immunotherapy combined with RT has shown significant clinical efficacy in treating patients with metastatic NSCLC, especially those with lung metastases and BMs. Preliminary results with multisite RT plus immunotherapy are also promising. However, further studies are needed to establish the safety and optimal regimen of this combination. Future research should focus on optimizing the radiation dose and fractionation, identifying predictive biomarkers, and developing novel immunotherapy agents and combinations. These efforts may improve survival and quality of life for patients with metastatic NSCLC.

Acknowledgments

The authors are grateful for the financial support from the Shandong Provincial Natural Science Foundation.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0018/rc

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Funding: This article was funded by the Shandong Provincial Natural Science Foundation (Nos. ZR2021QH356, ZR2021LSW023, and ZR2022MH103).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0018/coif). The authors have no conflicts of interest to declare.

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(English Language Editor: J. Gray)