Immune-preserving radiotherapy and perioperative immunotherapy in stage III NSCLC: a narrative review of current management and future directions for IIIA/IIIB NSCLC

Introduction

Clinical context and unmet needs in stage III non-small cell lung cancer (NSCLC)

Stage III NSCLC represents locally advanced disease without distant metastases, accounting for approximately 30% of NSCLC cases. Despite the absence of metastatic spread at diagnosis, clinical outcomes remain suboptimal. This stage encompasses a heterogeneous group of tumors characterized by varying tumor sizes, patterns of local invasion, and degrees of lymph node involvement. For instance, stage IIIA includes T3N1, T4N0, T1–2N2, and T4N1 disease subsets (1). For discussion purposes, we separate IIIA into two groups: IIIAr (resectable) and IIIAu (unresectable); IIIAu will be discussed alongside stages IIIB–C.

Due to this heterogeneity, management requires a multidisciplinary approach to tailor treatment strategies to individual patient characteristics. Although therapy is often administered with curative intent, overall survival (OS) remains limited. Data from the International Association for the Study of Lung Cancer (IASLC) global database (1999–2010) report 5-year OS rates of 36% to 41% for stage IIIA disease (2). With the transition to the American Joint Committee on Cancer (AJCC) 9th edition staging system, the boundaries of stage III subgroups are being refined; clinicians should be aware that some patients previously classified as IIIA may be reclassified, with implications for treatment selection and cross-trial comparisons (3).

Several fundamental questions remain unresolved in this disease setting. In the surgical domain, it remains unclear which patients with stage IIIA NSCLC are best served by surgical resection, whether patients with multi-station N2 disease benefit from resection in the immunotherapy (IO) era, and whether surgery is superior to concurrent chemoradiotherapy (cCRT) as definitive local therapy. Regarding systemic therapy, the optimal sequencing of IO—neoadjuvant versus adjuvant versus perioperative—is still being refined, and the role of targeted therapy in oncogene-driven stage III disease is evolving rapidly. In the radiotherapy (RT) arena, key questions include whether the incorporation of RT into neoadjuvant chemo-IO prior to surgical resection can enhance outcomes, and whether RT can be administered in a manner that modulates therapeutic immune responses while preserving systemic immune competence.

This review addresses these questions through a dual-track framework: Track 1 covers resectable stage IIIA disease, focusing on perioperative IO and surgical pathways; Track 2 addresses unresectable IIIA/IIIB disease, centering on the PACIFIC paradigm and immune-preserving RT strategies. Throughout both tracks, we distinguish between established evidence-based standards and investigational concepts still under evaluation. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1135/rc).

Methods

We conducted a narrative review of pivotal trials, prospective and retrospective cohorts, guidelines, and practice-shaping studies addressing stage III NSCLC (IIIA–IIIB). Electronic databases (PubMed/MEDLINE, Embase, Cochrane Library), trial registries (ClinicalTrials.gov), conference abstract libraries (ASCO, ESMO, ASTRO via meeting libraries), and professional guidelines (ASCO, ESMO, NCCN) were searched. An initial search was performed on September 1, 2025. An updated search was performed on March 1, 2026. The primary timeframe for inclusion was January 1, 2010 through March 1, 2026; seminal earlier trials were included when informative. Keywords for research were: non-small cell lung cancer, NSCLC, stage III, locally advanced lung cancer, chemotherapy, immunotherapy, surgery, radiation, chemoradiation, adjuvant, neoadjuvant, spatially fractionated radiation (SFRT). The inclusion criteria were: (I) English-language randomized controlled trial; (II) prospective or retrospective cohort; (III) meta-analysis; (IV) society guidelines. Articles were excluded if (I) small sample size less than 20 patients; (II) early-stage I–II NSCLC only; (III) stage IV NSCLC only; (IV) society guidelines without discussion of stage III NSCLC. No formal risk-of-bias tool was applied as this is a narrative review. We emphasized randomized evidence and large cohorts where available. Two reviewers, Z.C. and W.Y., independently screened titles/abstracts and full texts; disagreements were resolved by discussion. A detailed search strategy summary is provided in Table S1.

TRACK 1: resectable stage IIIA

Staging, resectability definitions, and surgical candidacy

Before discussing treatment strategies for resectable stage III NSCLC, it is essential to define key terms that influence both trial eligibility and real-world treatment selection. Two distinct concepts must be clearly separated:

Resectability refers to the anatomic and technical feasibility of achieving complete (R0) surgical resection, determined by tumor extent, airway and vascular involvement, and the number and location of involved lymph node stations. Operability, in contrast, refers to patient fitness for surgery, encompassing cardiopulmonary reserve, performance status, physiologic age, and comorbidities. A tumor may be technically resectable in a patient who is not operable, and vice versa. Both dimensions must be assessed in multidisciplinary tumor board discussions (4).

The definition of resectable disease in stage III NSCLC varies significantly across clinical trials, which complicates interpretation and cross-trial comparison of results. CheckMate 816 enrolled patients with resectable stage IB–IIIA NSCLC per AJCC 7th edition, with resectability determined by the treating surgeon. KEYNOTE-671 included stage II–IIIB (N2) disease per investigator assessment. AEGEAN enrolled stage IIA–IIIB (N2) per AJCC 8th edition. These differences mean that the “stage IIIA” populations across trials are not identical. The European Organisation for Research and Treatment of Cancer (EORTC) Lung Cancer Group has highlighted the need for standardized resectability criteria to enable meaningful cross-trial comparisons (4,5).

With the AJCC 9th edition staging system, several reclassifications affect stage III boundaries. Clinicians should be aware that patients who would have been classified as stage IIIA under prior editions may be reclassified, with implications for guideline-directed treatment. When evaluating trial data, attention to the staging edition used for enrollment is critical (3).

Surgical resection is generally considered for patients with T1–3 (select T4) tumors and limited nodal involvement (N0–1), T3N1, or select cases of T1–3N2 disease following neoadjuvant systemic therapy. A review of ten international guidelines evaluating management strategies for clinically diagnosed stage III N2 NSCLC prior to surgery revealed a consensus favoring multimodal treatment approaches incorporating either surgery or RT (5). In cases of non-bulky mediastinal lymph node involvement, most guidelines did not express a definitive preference between surgery and cCRT. However, as the extent and volume of N2 nodal disease increase, there is a greater inclination toward non-operative management with RT-based multimodal approaches. With increasing nodal burden, current guidelines increasingly support RT-centered treatment. Specifically, for patients with single-station, non-bulky N2 disease who demonstrate response to induction therapy, surgery remains a reasonable option; for multi-station or bulky N2 disease, definitive cCRT followed by consolidation IO is generally preferred. Notably, no uniform threshold for nodal volume has been established to guide surgical decision-making (5).

Perioperative IO: contemporary evidence

The integration of immune checkpoint inhibitors (ICIs) into perioperative regimens has transformed the management of resectable stage III NSCLC. Multiple phase III trials have now demonstrated significant improvements in pathological response rates and event-free survival (EFS), establishing perioperative IO as a new standard of care for eligible patients.

Neoadjuvant chemo-IO

The CheckMate 816 trial established the superiority of neoadjuvant chemo-IO over chemotherapy alone in resectable NSCLC. The addition of nivolumab to platinum-doublet chemotherapy significantly improved the pathological complete response (pCR) rate (24% vs. 2.2%) and EFS [median 31.6 vs. 20.8 months; hazard ratio (HR) 0.63]. These benefits were consistent across subgroups defined by programmed death-ligand 1 (PD-L1) expression and clinical stage, with the greatest magnitude of benefit observed in patients with stage IIIA disease. Updated analyses have confirmed an OS benefit, further solidifying the role of neoadjuvant nivolumab-chemotherapy in this setting (6,7).

Perioperative IO trials

Building on the neoadjuvant paradigm, several phase III trials have evaluated perioperative strategies combining neoadjuvant and adjuvant IO.

KEYNOTE-671 evaluated perioperative pembrolizumab (neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab) versus chemotherapy alone in patients with resectable stage II–IIIB (N2) NSCLC. The trial demonstrated significant improvements in EFS (HR 0.58) and OS (HR 0.72), with 24-month OS rates of 80.9% versus 77.6%. These results established perioperative pembrolizumab as a practice-changing regimen (8).

AEGEAN evaluated perioperative durvalumab in resectable stage IIA–IIIB (N2) NSCLC, demonstrating significant improvements in pCR (17.2% vs. 4.3%) and EFS (HR 0.68). The results support durvalumab as an additional perioperative IO option (9).

CheckMate 77T evaluated perioperative nivolumab (neoadjuvant nivolumab + chemotherapy followed by adjuvant nivolumab) in resectable stage IIA–IIIB NSCLC, demonstrating significant EFS improvement (HR 0.58) and a pCR rate of 25.3% versus 4.7% (10).

Neotorch evaluated perioperative toripalimab in resectable stage II–IIIA/B NSCLC in a Chinese population, reporting significant EFS benefit (HR 0.40) and a pCR rate of 24.8% versus 1.1% (11).

Collectively, these trials demonstrate consistent benefits of perioperative IO across different ICI agents, with pCR rates of 17–25% and significant EFS improvements. Importantly, perioperative IO has been shown to be safe and does not compromise surgical feasibility or quality. Table 1 summarizes the key trials, including study design, patient population, primary endpoint and key outcomes.

Neoadjuvant versus adjuvant IO sequencing

The optimal sequencing of IO relative to surgery remains an area of active investigation. No randomized trial in resectable NSCLC has directly compared neoadjuvant versus adjuvant IO. However, preclinical models have demonstrated superior efficacy of neoadjuvant over adjuvant ICI administration, and randomized data in melanoma have similarly shown that perioperative pembrolizumab confers greater benefit than adjuvant treatment alone (22).

In the adjuvant-only setting, the IMpower010 trial demonstrated that adjuvant atezolizumab significantly extended disease-free survival (DFS) compared to best supportive care in patients with resected stage II–IIIA NSCLC expressing PD-L1 ≥1% (HR 0.66) (18). The PEARLS/KEYNOTE-091 trial demonstrated a significant DFS benefit with adjuvant pembrolizumab in a PD-L1-unselected population of stage IB–IIIA NSCLC (HR 0.76) (19).

A National Cancer Database analysis of patients undergoing surgery for stage II–IIIB NSCLC between 2015 and 2020 suggested superior OS with neoadjuvant versus adjuvant chemo-IO [IPW-adjusted HR 0.70; 95% confidence interval (CI): 0.50–0.96]. Notably, a higher proportion of stage IIIA and IIIB patients received neoadjuvant treatment compared to adjuvant therapy, consistent with existing practice patterns (20). The biological rationale for neoadjuvant IO includes the concept that the intact tumor and primary lymphatics facilitate better T-cell priming, with the tumor acting as an antigen source for T-cell expansion and systemic immune surveillance targeting micro-metastases (23).

Surgery versus cCRT as definitive local therapy

The choice between surgery and cCRT as definitive local therapy is a critical decision that determines the subsequent IO integration strategy: perioperative IO for surgical candidates versus consolidation IO (the PACIFIC paradigm) for cCRT candidates. Direct randomized comparisons remain limited.

The Intergroup 0139 trial randomized patients with potentially resectable stage IIIA (N2) NSCLC to either cCRT alone or induction cCRT followed by surgery. No significant OS difference was observed between groups (27.2% vs. 20.3% at 5 years), although progression-free survival (PFS) was improved with surgery. An unplanned post hoc analysis revealed a survival advantage for patients undergoing lobectomy (36% vs. 18% at 5 years, P=0.002), but worse outcomes for those requiring pneumonectomy (13). A meta-analysis incorporating INT 0139 and the Nordic SORENSEN study reported a non-significant survival benefit for trimodality therapy (HR 0.87; 95% CI: 0.75–1.01; P=0.068) (12,24).

Following the PACIFIC trial, which demonstrated a 5-year OS of 42.9% with consolidation durvalumab after cCRT (25), the optimal definitive treatment approach has become a subject of renewed debate. Current data suggest that in appropriately selected patients—especially those with limited disease burden who are amenable to lobectomy—surgical management may offer a survival benefit. However, there is likely considerable selection bias in retrospective surgical series, and the absence of contemporary randomized trials comparing surgery with perioperative IO versus cCRT with consolidation IO underscores the need for personalized, multidisciplinary decision-making (26). Patients who do not achieve meaningful mediastinal downstaging after induction therapy are generally better served by definitive cCRT followed by consolidation durvalumab.

Oncogene-driven disease: targeted therapy considerations

Molecular testing at diagnosis is essential for all patients with stage III NSCLC, as oncogene-driven tumors (EGFR, ALK, ROS1, BRAF, and others) may benefit from targeted therapy approaches rather than, or in addition to, IO. Most perioperative IO trials excluded patients with known EGFR mutations or ALK rearrangements, and the benefit of ICIs in oncogene-driven tumors is generally reduced compared to wild-type disease.

In the resectable setting, the EMERGING-CTONG 1103 trial evaluated neoadjuvant erlotinib versus chemotherapy in stage IIIA-N2 EGFR-mutant NSCLC, demonstrating improved PFS (21.5 vs. 11.4 months), with a numerically longer but not statistically significant median OS (42.2 vs. 36.9 months; P=0.51) (17). In the unresectable setting, the LAURA trial demonstrated that maintenance osimertinib after cCRT significantly improved PFS in patients with unresectable stage III EGFR-mutant NSCLC (median PFS 39.1 vs. 5.6 months; HR 0.16), establishing a new standard for this molecular subgroup (27). These data underscore the importance of reflexive molecular testing at diagnosis to guide systemic strategy selection, as the optimal treatment approach for oncogene-driven stage III NSCLC differs fundamentally from that of wild-type disease.

Translational horizons: failure patterns, tumor-infiltrating lymphocyte (TIL) biology, and RT-as-immune-priming

Patterns of failure in resectable IIIA

Despite advancements in local control, the primary cause of failure and mortality in resectable IIIA disease is distant organ metastases. Among patients with completely resected stage IIIA(N2) NSCLC who did not receive postoperative RT, 64.7% of recurrences presented as distant metastases while 32.1% were locoregional failures. Similarly, in patients treated with cCRT and consolidation ICIs, isolated distant failure was the most common pattern (31%), compared to isolated locoregional failure at 8.7% (28,29). These data indicate that approximately 70% of failures result from occult micrometastatic dissemination at the time of surgery, and improvements in systemic therapy are needed to address this dominant mode of failure.

TILs and the tumor microenvironment (TME)

The overall response rate (ORR) to single-agent IO in NSCLC remains modest at approximately 20–30%, and the TME plays a critical role in determining responsiveness. TILs in resected NSCLC specimens are robustly and independently associated with ICI treatment response (30). A high density of TILs has been linked to improved OS and reduced distant metastases in patients with pathologic stage IIIA(N2) disease following complete surgical resection (31). These observations provide a biological rationale for strategies that enhance TIL infiltration and for utilizing surgically resected specimens to characterize the immune landscape.

Incorporating cellular therapy into IO in NSCLC: an investigational approach

It is important to emphasize that cellular therapy approaches in NSCLC, including TIL therapy, remain highly investigational with very limited clinical evidence to date. TIL therapy harnesses the patient’s immune system by isolating TILs from the TME, expanding them ex vivo, and re-infusing them to enhance antitumor immune responses (32). The first clinical trial evaluating adoptive TIL therapy in the postoperative setting for stage II–IIIB NSCLC was published in 1996. More recently, a phase I trial (NCT03215810) assessed autologous TILs combined with nivolumab in patients with advanced NSCLC progressing on prior anti-programmed death-1 (PD-1) therapy; of 13 evaluable patients, three had confirmed responses and 11 had some reduction in tumor burden, including two complete responses ongoing at 1.5 years (33).

The IOV-COM-202 trial (NCT03645928) evaluated lifileucel in solid tumors. Among ICI-naïve patients with metastatic NSCLC, lifileucel plus pembrolizumab achieved an ORR of 42.1%, rising to 58.3% in EGFR wild-type, PD-L1-negative subgroups. In ICI-pretreated patients, lifileucel monotherapy yielded an ORR of 21.4% (34,35). However, several important limitations temper enthusiasm for this approach: lifileucel monotherapy costs approximately $500,000 per treatment; the manufacturing process requires adequate tumor tissue and several weeks of ex vivo expansion; and lymphodepletion conditioning is required prior to infusion. These practical and economic barriers, combined with modest monotherapy response rates, indicate that TIL therapy is unlikely to become a routine treatment modality in the near term. Nevertheless, in patients who undergo surgical resection for other clinical indications, the opportunity to obtain tissue for molecular profiling and, within the context of clinical trials, TIL expansion represents a potential translational opportunity that warrants further investigation.

RT as an immune-priming tool

RT can be employed not only as a direct cytotoxic modality but also as an agent that modulates the tumor immune microenvironment. Stereotactic body radiation therapy (SBRT) can enhance T-cell receptor (TCR) repertoire diversity, increase PD-L1 expression in the TME, and induce neo-mutations in tumor cell genes (36). Spatially fractionated radiation therapy (SFRT), which delivers a high ablative dose to a small partial volume within a tumor while limiting peripheral doses, has been shown to modulate the tumor immune microenvironment through secretion of inflammatory cytokines and increased immune cell infiltration (37). Low-dose radiation therapy (LDRT) has been shown to reprogram the immunosuppressive TME, enabling effector cell infiltration and synergistically enhancing antitumor responses (38).

In a randomized phase II trial, neoadjuvant durvalumab combined with SBRT (3 fractions of 8 Gy to the primary tumor) was compared with durvalumab alone in patients with resectable early-stage NSCLC. The combination arm achieved a significantly higher major pathological response (MPR; 53.3% vs. 6.7%), with a numerically higher 3-year disease-free survival (67% vs. 63%) that was not statistically significant (21). These findings suggest a promising translational strategy whereby localized high-dose RT may act as an immunologic adjuvant. However, these results require validation in larger, adequately powered trials before incorporation into routine practice.

In summary, there are multiple evolving treatment approaches in managing resectable locally advanced NSCLC. The optimal treatment strategy is still under active investigation. Figure 1 illustrates a comprehensive treatment paradigm and opportunities for future research.

Figure 1 A comprehensive treatment paradigm and evolving opportunities for managing resectable locally advanced NSCLC. Created in BioRender. Yan, W. (2026) https://BioRender.com/6b0szob. ICI, immune checkpoint inhibitor; NSCLC, non-small cell lung cancer; TIL, tumor-infiltrating lymphocyte; XRT, external beam radiation therapy.

TRACK 2: unresectable IIIA–B

Concurrent chemoradiation and consolidation IO

For patients with NSCLC presenting with unresectable N2 (stage IIIA) or N3 (stage IIIB) lymph nodes, cCRT remains the foundation of curative-intent treatment. The transition from the surgical to the non-surgical track is determined by the resectability and operability assessments discussed in section “Staging, resectability definitions, and surgical candidacy”.

Historically, platinum-based chemotherapy was the primary systemic therapy for stage III NSCLC regardless of resectability, offering only a marginal absolute survival benefit of approximately 5% at 5 years compared to placebo (HR 0.84 neoadjuvant; HR 0.83 adjuvant) (39). Contemporary outcomes with platinum-based cCRT without IO have improved substantially compared to older series. In RTOG 0617, the 5-year OS in the standard-dose (60 Gy) cCRT arm was 32.1% (40). In the PACIFIC trial placebo arm (cCRT alone), the 5-year OS was 33.4% (25). These contemporary benchmarks should be used when evaluating the incremental benefit of IO additions, rather than the older 10–20% 5-year survival figures that reflected earlier-era treatment.

The PACIFIC paradigm

The PACIFIC trial established the role of consolidation IO in unresectable stage III NSCLC, demonstrating that durvalumab after cCRT significantly improved both PFS and OS, with a reported 5-year OS rate of 42.9% versus 33.4% with placebo (25). The current standard of care includes platinum-based chemotherapy administered concurrently with thoracic RT at a dose of 60–66 Gy, followed by up to 12 months of durvalumab in patients without disease progression (41,42). This paradigm has also influenced decision-making for patients with N2 disease who might otherwise have been considered for surgery, as the robust survival benefit of cCRT followed by durvalumab provides a strong non-surgical alternative for patients with borderline resectability.

For patients with EGFR-mutant unresectable stage III NSCLC, the LAURA trial demonstrated that maintenance osimertinib after cCRT dramatically improved PFS compared to placebo (median 39.1 vs. 5.6 months; HR 0.16), establishing a targeted therapy paradigm for this molecular subgroup that is distinct from the durvalumab consolidation approach used in wild-type disease (27).

Challenges and pitfalls of RT in stage III NSCLC

Inadequate dose to tumor

RT requires a careful balance between delivering cytotoxic doses to the tumor and minimizing exposure to nearby healthy tissues. The primary role of thoracic RT in stage III NSCLC is direct tumor cell kill—it remains, first and foremost, a cornerstone for local tumor control. Evidence from SBRT trials has shown that biologically effective doses (BED) exceeding 100 Gy consistently result in local control rates above 90% in early-stage NSCLC (43). In patients with resectable stage III NSCLC treated with cCRT, fewer than half achieve pathologic locoregional control, and radiation doses of 60 Gy achieve pCR in only approximately 35% of patients (44,45).

However, the RTOG 0617 trial demonstrated that uniform dose escalation from 60 Gy to 74 Gy did not improve survival and was paradoxically associated with increased treatment-related mortality. The 5-year OS was 32.1% in the 60 Gy arm versus 23.0% in the 74 Gy arm (40). This finding underscores that simple dose escalation with conventional fractionation is not a viable strategy for improving outcomes. More sophisticated, biologically guided dose escalation approaches—such as targeted boosts to residual disease—are under investigation but have not yet been validated in phase III trials.

Cardiac irradiation: beyond cardiotoxicity to immune implications

The RTOG 0617 findings sparked extensive research into the effects of cardiac radiation exposure. A key question is what explains the decreased survival with higher radiation doses beyond overt cardiac toxicity. Population-based SEER data indicated that the 2-year cardiac death rate of approximately 4% was insufficient to explain the 13% survival difference observed in RTOG 0617 (46). A large single-institution study similarly found that among 533 deaths, only 5.1% were cardiac-related, while 67.0% were due to lung cancer (47). These data suggest that cardiac mortality alone does not account for the increased mortality observed with high-dose RT.

Voxel-based analysis (VBA) techniques have identified dose-sensitive regions within the heart, particularly at the base—anatomically corresponding to the origin of the left coronary artery and the sinoatrial (SA) node. Multivariable modeling showed that the previously observed survival detriment in RTOG 0617 was no longer statistically significant once the dose to this critical cardiac subregion was included in the model (48). Emerging evidence suggests that radiation affecting vascular and immunologically active structures within the heart may lead to systemic immune suppression and diminished treatment efficacy (49). These findings have direct implications for immune-preserving RT planning strategies, as they suggest that sparing specific cardiac substructures may preserve not only cardiac function but also immune competence.

Thoracic RT and immune depletion

The effective dose to immune cells (EDIC) is a significant independent predictor of poor OS and local progression-free survival (LPFS) in patients with stage III NSCLC treated under RTOG 0617, underscoring the critical role of radiation dose to circulating immune cells for tumor control (50). Studies examining the estimated dose of radiation to immune cells (EDRIC) found a correlation between planning target volume (PTV) and EDRIC (P=0.0004), with higher EDRIC linked to an increased incidence of grade 3 or higher lymphopenia (HR 3.30, P=0.004) (51,52). Severe radiation-induced lymphopenia (RIL) significantly attenuates the survival benefits of durvalumab consolidation therapy following cCRT for NSCLC, highlighting that strategies to mitigate RIL could potentially enhance ICI efficacy (53).

RT that preserves immunity: immune organ-at-risk (iOAR)/EDIC concepts and planning strategies

Given the evidence that RT-induced immune depletion adversely affects outcomes, particularly in the era of consolidation IO, several strategies have been proposed to preserve immune competence during thoracic RT. It is critical to emphasize that these approaches should be pursued only when they do not compromise tumor coverage or dose adequacy—tumor control remains the primary objective of RT.

iOAR-aware RT planning

While the heart and major vessels are routinely contoured as organs at risk (OARs) in thoracic RT planning, lymphocyte-rich structures—including uninvolved lymph nodes, the thoracic duct, thymus, and specific cardiac substructures implicated in immune regulation (such as the SA node region)—are not yet systematically classified as iOARs in standard planning protocols. Improving the understanding and integration of iOARs into RT planning is a crucial step in addressing radiation-induced immunosuppression (54). Current models, such as the EDIC, have shown prognostic significance for OS and PFS by estimating the radiation dose delivered to circulating lymphocytes based on blood flow dynamics (52). However, these models rely on simplifying assumptions and often overlook critical contributors to immune function, such as lymphatic structures, thoracic duct, thymus, and bone marrow.

To address these limitations, advanced analytical and Monte Carlo-based models are being developed to more accurately quantify both in-field and out-of-field radiation exposure (55). Novel computational frameworks incorporating artificial intelligence are under exploration to simulate immune system dynamics and predict immunologic outcomes based on dose-response modeling (56,57). Representative iOAR-aware planning approaches are illustrated in Figure 2.

Figure 2 Three complementary thoracic radiation strategies integrating iOAR sparing: (A) SBRT to the primary tumor with explicit iOAR-aware heart sparing; (B) mediastinal hypofractionated external-beam RT with iOAR sparing to minimize lymphocyte dose; (C) SCART/SFRT to a bulky primary for cytoreduction and immune priming, combined with mediastinal hypofractionated RT and heart-sparing iOAR protection. iOAR, immune organ-at-risk; RT, radiotherapy; SBRT, stereotactic body radiation therapy; SCART, stereotactic centralized ablative radiation therapy; SFRT, spatially fractionated radiation therapy.

Hypofractionation to reduce cumulative immune damage

Hypofractionation—delivering the therapeutic dose in fewer, larger fractions—may help reduce cumulative damage to the circulating lymphocyte pool. Although individual fraction damage to directly irradiated lymphocytes may be greater with higher dose-per-fraction, the total cumulative dose to circulating immune cells depends critically on repeated exposure over time. With 30 daily fractions of conventional RT, circulating lymphocytes are repeatedly exposed to low-dose bath radiation over 6 weeks; each fraction provides another opportunity for lymphocyte kill as blood circulates through the treatment field. The EDIC model explicitly incorporates the number of fractions as a determinant of cumulative immune cell dose, as more fractions mean more passes of circulating blood through irradiated volumes (50,52). Hypofractionation reduces the total number of exposures and the overall treatment time, potentially reducing cumulative damage to the circulating lymphocyte pool.

Clinical evidence supports the feasibility of hypofractionated regimens in stage III NSCLC. A phase 3 randomized trial comparing hypofractionated image-guided RT (60 Gy in 15 fractions) with conventional fractionated RT (60 Gy in 30 fractions) in stage II/III NSCLC patients with poor performance status showed no significant differences in median OS, PFS, or grade ≥3 toxicity (58). A more recent trial demonstrated that concurrent chemoradiation with an adaptive SABR boost aiming for a total of 70 Gy in 15 fractions was safe and effective for patients with locally advanced, unresectable NSCLC (59). These data suggest that mediastinal radiation can potentially be delivered in 10–15 fractions instead of 30, with the potential benefit of reduced cumulative immune cell damage.

Reducing radiation exposure to immune-active cardiac substructures

Since RT for N2 disease involves mediastinal irradiation, which naturally exposes the base of the heart and aorta to radiation, efforts should be made to spare immune cells and immune-active structures. Techniques such as intensity-modulated RT (IMRT) and proton therapy can be employed to reduce dose to the heart base and SA node region while maintaining adequate target coverage.

Surgical approaches to mediastinal disease management may also contribute to reducing radiation volumes. Transcervical extended mediastinal lymphadenectomy (TEMLA) and video-assisted mediastinoscopic lymphadenectomy (VAMLA) were originally developed for staging but have evolved into therapeutic procedures (60,61). In selected cases, surgical debulking of metastatic mediastinal nodes via TEMLA/VAMLA could reduce the volume requiring radiation, thereby reducing the dose to immune-active structures. A pilot study demonstrated that combining TEMLA with single-fraction SBRT (10 Gy) achieved excellent local control with potentially less immune system damage compared to 60 Gy in 30 fractions (62). However, the role of extensive mediastinal lymphadenectomy in the IO era is uncertain and potentially controversial. Uninvolved lymph nodes serve as critical sites for antigen presentation and T-cell priming, and their preservation may be important for IO efficacy. Any surgical strategy must carefully balance disease clearance against preservation of the immune-priming infrastructure. These approaches remain investigational and require prospective evaluation.

Strategic use of hypofractionation, SBRT/SFRT, and boost concepts

Approaches to improve primary tumor control

Despite employing dose escalation (60–81.9 Gy) and conformal techniques, approximately 35% of patients experience disease recurrence within the PTV, with nearly half occurring within the first year (63). The NRG Oncology phase III randomized LU008 trial is currently assessing whether replacing conventionally fractionated RT with SBRT to the primary tumor, followed by concurrent chemoradiation to the mediastinum, will improve OS and PFS (64). It is important to emphasize that this approach is investigational and awaiting phase III validation.

The use of SBRT for central and ultra-central tumors—particularly when combined with systemic therapy—raises important safety concerns, including risks of bronchial toxicity, fistula formation, and hemorrhage. When full-dose SBRT is not suitable due to centralized disease, an SBRT boost (6.5 Gy × 3 fractions, 19.5 Gy total) for medial tumors has been performed using RTOG 0813 dose constraints without reported toxicities, but long-term safety data with concurrent IO are limited (65). Dose escalation has not demonstrated benefit in stage III NSCLC when applied uniformly (as shown in RTOG 0617), and any boost or dose-escalation strategy must be pursued within the framework of prospective clinical trials with rigorous safety monitoring.

SFRT: spatially fractionated approaches

SFRT is a radiation technique that limits ablative doses to tumor subvolumes, creating a highly heterogeneous dose distribution. Preclinical data suggest that this dose heterogeneity may increase immune-rich infiltrate within the targeted tumor, with enhanced antigen presentation and activated T cells (38,66). Radiobiological studies have demonstrated that partial tumor irradiation can increase CD3⁺ cells and TRAIL within the tumor (67), and intratumoral radiation dose heterogeneity has been shown to augment antitumor immunity in mouse models (68). However, clinical evidence in NSCLC remains very limited, and these approaches should be considered investigational.

Minibeam radiotherapy (MBRT) and FLASH-RT

MBRT employs spatially fractionated radiation through narrow, parallel beams (0.3–1 mm width), creating a pattern of high-dose “peaks” and low-dose “valleys”. Preclinical studies indicate that MBRT mitigates radiation-induced lung injury while maintaining tumor control, suggesting potential for safe dose escalation (69,70). FLASH-RT, defined by ultra-high dose rates (≥40 Gy/s), enables the entire therapeutic dose to be delivered in milliseconds. The “FLASH effect” may reduce normal tissue toxicity while maintaining antitumor efficacy, hypothesized to result from transient oxygen depletion during irradiation (71). Early-phase clinical trials are investigating FLASH-RT for thoracic malignancies, including NSCLC (72). Both MBRT and FLASH-RT remain in early development and are not available for routine clinical use.

Figure 2 illustrates three complementary thoracic radiation strategies integrating iOAR sparing: (A) SBRT to the primary tumor with explicit iOAR-aware heart sparing; (B) mediastinal hypofractionated external-beam RT with iOAR sparing to minimize lymphocyte dose; (C) stereotactic centralized ablative radiation therapy (SCART)/SFRT to a bulky primary for cytoreduction and immune priming, combined with mediastinal hypofractionated RT and heart-sparing iOAR protection. These modalities can be used alone or sequentially depending on tumor location and nodal burden.

Proposed treatment approaches by clinical scenario

Based on the evidence reviewed, the following investigational approaches may be considered within the context of clinical trials or multidisciplinary discussion, in addition to established standards of care.

For unresectable disease with peripheral primary lesions (3–7 cm), SBRT to the primary site following standard BED ≥100 Gy may be considered per the LU008 paradigm (investigational). For centrally located tumors near nodal disease or primary tumors larger than 7 cm, SFRT approaches (2–3 treatments of 18 Gy each to the tumor core with simultaneous integrated boost) are under investigation. For mediastinal disease, hypofractionation and/or iOAR-based planning should be considered to reduce immune depletion, with or without SBRT boost (6.5 Gy × 3 fractions). All such dose-escalation and novel fractionation strategies should be pursued within the framework of prospective trials with appropriate safety monitoring.

Conclusions

The management of stage III NSCLC continues to evolve, anchored by a dual-track algorithm that remains the evidence-based standard: perioperative chemo-IO for operable IIIA disease and cCRT followed by durvalumab for unresectable IIIA/IIIB disease. For patients with oncogene-driven tumors, targeted therapy approaches (e.g., osimertinib after cCRT for EGFR-mutant disease) represent an important alternative paradigm.

Tumor control remains the primary objective of thoracic RT, which is first and foremost a cornerstone for direct tumor cell kill. Within this framework, refinements that aim to preserve immune competence—including iOAR-aware RT planning, judicious hypofractionation, and minimization of low-dose bath to circulating lymphocytes—represent promising areas of investigation. These immune-preserving strategies should be pursued only when they do not compromise tumor coverage or dose adequacy.

When surgical resection is performed for appropriate clinical indications, the opportunity to obtain tissue for comprehensive molecular profiling and, in the context of clinical trials, TIL expansion may support personalized treatment strategies. However, TIL therapy and other cellular approaches remain highly investigational, with high cost and practical barriers, and should not drive primary treatment decisions.

Several key questions warrant prospective investigation: the comparative efficacy of surgery with perioperative IO versus cCRT with consolidation IO in the contemporary era; the incremental benefit of iOAR-aware RT planning on immune preservation and clinical outcomes; the role of hypofractionated regimens and SBRT/SFRT boost strategies in improving the therapeutic ratio; and the optimal integration of emerging modalities such as FLASH-RT and cellular therapies. Answering these questions will require well-designed prospective trials and continued multidisciplinary collaboration.

Acknowledgments

The views expressed are those of the authors and do not necessarily represent those of the Ohio State University, University of Kentucky or affiliated institutions. Language polishing was assisted by AI tools; all scientific content and conclusions were authored and verified by the authors.

Footnote

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1135/coif). C.S. reports leadership role in thoracic oncology with the American Society for Radiation Oncology, American Radium Society, and Proton Collaborative Group. The other authors have no conflicts of interest to declare.

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