The role of radiotherapy for the immunotherapy of esophageal squamous cell carcinoma: translational approach and future pathways—a narrative review

Introduction

Esophageal cancer is the 11^th most frequently diagnosed malignancy and ranks as the 7^th leading cause of cancer-related mortality worldwide (1). Esophageal cancer is divided into two major histological subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC remains the predominant subtype globally, accounting for approximately 85% of cases in 2020 (2,3). Multimodal treatment approaches, including surgery, chemotherapy, and radiotherapy (RT), have been developed to improve outcomes in esophageal cancer, with treatment strategies differing between ESCC and EAC (4-11). In resectable esophageal cancer, the CROSS trial established preoperative chemoradiotherapy (CRT) as a standard of care, demonstrating superior outcomes compared with surgery alone in both adenocarcinoma and squamous cell carcinoma (SCC) (4). However, in adenocarcinoma, subsequent phase III trials such as NEO-AEGIS and ESOPEC have shown that perioperative chemotherapy with regimens such as FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) may be superior to preoperative CRT (5,6), leading to perioperative chemotherapy being adopted as the preferred standard of care in Western guidelines. In contrast, for locally advanced ESCC, both preoperative CRT and definitive CRT (dCRT) are established standards of care (4,12-15). However, the long-term survival of patients with locally advanced ESCC treated with CRT remains suboptimal, highlighting the need for more intensive treatment strategies.

In the metastatic setting, several phase III trials have demonstrated significant survival benefits from adding immune checkpoint inhibitors (ICIs) to chemotherapy, thereby establishing this approach as a standard of care (8-10). Meanwhile, trials combining RT with ICI have been conducted across various malignancies (16-33), and similar strategies are now being actively explored in advanced ESCC (34-38).

This narrative review will examine the role of combining RT with ICI in patients with advanced ESCC, providing a comprehensive overview of evidence from the recently reported key phase III SKYSCRAPER-07 trial (35), as well as phase II studies with a particular focus on those incorporating translational research. We present this article in accordance with the Narrative Review reporting checklist (available at https://aoe.amegroups.com/article/view/10.21037/aoe-2025-1-46/rc).

Methods

In this narrative review, a literature search was conducted on October 31, 2025, using PubMed and ClinicalTrials.gov (Table 1). The search strategy included the terms “esophageal squamous cell carcinoma” AND (“radiotherapy” OR “chemoradiotherapy”) AND (“immune checkpoint inhibitor” OR “PD-1” OR “PD-L1”), covering all available years from inception through October 2025. Case reports were excluded. Eligible studies included meta-analyses, systematic reviews, randomized controlled trials, cohort studies, review papers, and relevant clinical practice guidelines or consensus statements, which were selected according to their quality and relevance as determined by the authors. Only publications written in English were considered. Given the nature of this article, approval from an institutional review board was not required.

Therapeutic paradigm evolution of ICIs in ESCC

The clinical landscape of ESCC has been revolutionized by the advent of ICI over the past decade. The introduction of ICI has reshaped treatment paradigms across multiple settings, from metastatic disease to postoperative adjuvant therapy in esophageal cancer.

In metastatic or unresectable locally advanced ESCC, the clinical development of ICI has transformed systemic therapy across multiple treatment lines. The phase III KEYNOTE-181 trial first established the clinical relevance of ICI in advanced esophageal cancer, demonstrating a significant overall survival (OS) benefit of pembrolizumab, an anti-PD-1 antibody, over chemotherapy in patients with PD-L1 combined positive score (CPS) ≥10 (39). This finding positioned ICI as a viable therapeutic option in the second-line setting. Subsequently, the phase III ATTRACTION-3 trial confirmed the efficacy of nivolumab, an anti-PD-1 antibody, monotherapy regardless of PD-L1 expression, leading to its global approval as a second-line standard of care (40). Building on these advances, the phase III KEYNOTE-590 and CheckMate 648 trials expanded the role of ICI to the first-line setting. In KEYNOTE-590, pembrolizumab combined with chemotherapy significantly improved OS compared with chemotherapy alone, particularly among patients with PD-L1 CPS ≥10 (8). Similarly, CheckMate 648 demonstrated superior survival with both nivolumab plus chemotherapy and nivolumab plus ipilimumab, an anti-CTLA-4 antibody, compared to chemotherapy alone, establishing immune-based combination regimens as new first-line standards for advanced ESCC (9). Further refinement came with the phase III RATIONALE-302 and RATIONALE-306 trials evaluating tislelizumab, another anti-PD-1 antibody. RATIONALE-302 confirmed the benefit of tislelizumab monotherapy as second-line or later treatment (41), while RATIONALE-306, conducted in the first-line setting, demonstrated a significant survival benefit with tislelizumab plus chemotherapy compared with chemotherapy alone (10), reinforcing the efficacy of ICI across diverse global populations.

The success of ICIs in esophageal cancer has sparked interest in combining them with RT. The CheckMate 577 trial was the first phase III study to demonstrate the synergistic effect of RT and ICI in resectable locally advanced esophageal cancer (34,42). In patients with resected stage II/III esophageal or gastroesophageal junction cancer following neoadjuvant CRT, adjuvant nivolumab doubled median disease-free survival (DFS) compared with placebo, establishing a new global standard of care and demonstrating the sequential benefit of ICI after RT even in esophageal cancer, as observed in other tumor types (16,18,19,27,31).

Taken together, these developments have led to the widespread incorporation of ICI into the treatment of esophageal cancer.

Immunoradiotherapy: exploring the synergistic potential of RT and ICI

The combination of RT and ICI is now widely employed across various malignancies, and several hypotheses underpin the rationale for this combination as a promising therapeutic strategy. First, tumor-associated proteins released following radiation-induced cell damage can be recognized by antigen-presenting cells, which in turn initiate and activate cytotoxic T lymphocytes (43). In this way, radiation has the potential to elicit an antitumor immune response. Additional effects of this combination include the induction of pro-inflammatory signaling and modulation of the tumor microenvironment (TME) (44,45). A growing body of evidence has also shown that this approach can potentiate the abscopal effect and promote antitumor immune memory, ultimately contributing to improved therapeutic outcomes (46-48). Moreover, RT activates the cGAS-STING pathway, a cytosolic DNA sensor that triggers innate immune responses, resulting in increased type I interferon and PD-L1 expression (49,50). Taken together, these findings indicate that RT can convert immunologically “cold” tumors into “hot” tumors by remodeling the TME toward an immune-activated state, thereby enhancing sensitivity to ICI therapy. In clinical practice, even in ESCC, activation of the cGAS-STING pathway and upregulation of type I interferon and PD-L1 have been observed following CRT (51), suggesting that ICIs may exert synergistic effects when administered either concurrently with or sequentially after RT (52).

RT and immunotherapy: synergizing strategies in ESCC

RT and ICI combination therapy has been investigated across various settings in ESCC. This section provides an overview of clinical trials evaluating this approach in the locally advanced setting—both preoperative chemoradiotherapy and dCRT—as well as in the metastatic setting (Tables 2-4).

Preoperative immunoradiotherapy in locally advanced ESCC

The PALACE-1 trial was a phase II study conducted in China to evaluate the feasibility and safety of adding pembrolizumab to standard preoperative CRT in patients with resectable locally advanced ESCC (cT2–4a, any N, M0; stage II–IVA) (53). Among 20 patients, 19 (95%) completed preoperative treatment and 18 (90%) underwent surgery, with a pathological complete response (pCR) rate of 55.6% (10/18) and an R0 resection rate of 94%. Notably, immune profiling suggested that increased infiltration of TCF1⁺ CD8⁺ T cells was associated with higher pCR rates, highlighting their potential as a biomarker of response.

The SCIENCE trial is an ongoing multicenter randomized phase III study designed to evaluate the role of sintilimab, an anti-PD-1 antibody, in the neoadjuvant setting for resectable locally advanced ESCC (54,55). Eligible patients had thoracic ESCC staged as cT1N2–3M0 or cT2–4aN0–3M0, corresponding to stage III disease. Between November 2022 and June 2024, 146 patients were enrolled and randomized in a 1:1:1 ratio into three groups: Group A, neoadjuvant chemotherapy (nab-paclitaxel + carboplatin) plus sintilimab; Group B, neoadjuvant CRT (41.4 Gy/23 fractions with concurrent nab-paclitaxel + carboplatin) plus sintilimab; and Group C, standard neoadjuvant CRT alone. The primary endpoints are pCR rate and event-free survival (EFS), and preliminary results were presented at the American Society of Clinical Oncology (ASCO) 2025. All patients completed neoadjuvant therapy and underwent surgery, achieving a 100% R0 resection rate. Marked differences in pCR rates were observed: 13%, 60%, and 47.3% in Groups A, B, and C, respectively. Both Groups B and C demonstrated significantly higher pCR rates compared with Group A (P<0.0001 and P=0.0005, respectively); however, since the statistical comparison was primarily focused on Groups A and B against the reference, and the original control arm was Group C, the interpretation of these findings requires caution due to potential study design biases. In addition, the median duration of surgery was relatively short across groups: 4.2, 4.4, and 4.0 hours in Groups A, B, and C, respectively, raising concerns about whether sufficient lymph node dissection was consistently achieved. Moreover, pulmonary complications were frequent, occurring in 67.4%, 44.4%, and 47.3% of patients in Groups A, B, and C, respectively. Given the statistical design limitations and these perioperative findings, definitive conclusions regarding the added benefit of ICI to CRT are difficult to draw based on the current data, and longer follow-up, including EFS outcomes, will be essential to clarify its clinical benefit.

The iCROSS trial is a multicenter prospective randomized phase II/III trial (n=67) comparing neoadjuvant CRT plus tislelizumab vs. neoadjuvant CRT alone in patients with resectable locally advanced ESCC (cII–III stage) (56). The primary endpoints were pCR rate and OS. In the interim analysis, pCR results were reported, showing no significant difference between the combination therapy group and the control group (41.4% vs. 30.8%, P=0.414). Safety profiles were comparable between the two groups with no significant safety concerns observed. The OS results are still pending, and long-term follow-up data are eagerly awaited.

The NEXUS-1 trial was a phase II study conducted in China to evaluate conversion therapy for patients with unresectable locally advanced ESCC (57). Thirty patients with cT3–4 disease, predominantly stage III–IVa, received CRT (50 Gy/25 fractions with weekly nab-paclitaxel and cisplatin) followed by two cycles of tislelizumab-based immunochemotherapy, and surgery was performed in patients who were converted to resectable status. The primary endpoint of 1-year progression-free survival (PFS) was met, achieving 79.4% at a median follow-up of 21 months, with 1-year OS of 89.6%. Twenty-one patients proceeded to surgery with an R0 resection rate of 95.2% and a pCR rate of 43.3%. Five patients (20.8%) developed immune-related pneumonitis, including 2 with grade 3 toxicity, though 4 cases resolved with treatment allowing subsequent surgery. In this study, NRF2 pathway mutations were identified in 6 patients (21.4%) using circulating tumor DNA (ctDNA) analysis and were associated with significantly worse outcomes [median PFS: 8.5 months vs. not reached, hazard ratio (HR) =3.11, P=0.06; median OS: 13.4 months vs. not reached, HR =4.04, P=0.05]. In multivariable analysis, NRF2 mutations remained an independent adverse prognostic factor (PFS: HR =3.81, P=0.05; OS: HR =3.86, P=0.11). These findings suggest that sequential immunochemotherapy following CRT, and subsequent conversion surgery, may represent a promising treatment strategy for unresectable locally advanced ESCC, with high rates of R0 resection and pCR. Furthermore, ctDNA-based biomarkers such as NRF2 mutations may help identify patients at higher risk for treatment resistance.

In resectable locally advanced ESCC, preoperative CRT combined with ICI has shown favorable outcomes. While the phase III SCIENCE trial demonstrated promising results in terms of pCR rates, the phase II/III iCROSS trial failed to show a significant difference. Several other phase III trials are currently ongoing, and the results of these studies are needed to clarify the true benefit of this treatment approach in this setting. Although most ongoing studies are designed with subsequent surgery, the results of JCOG1109 demonstrated that the increased pCR rate after preoperative CRT was not associated with OS in resectable locally advanced ESCC (7). How these findings will translate in the context of CRT and ICI remains uncertain. At present, the field must await mature survival outcomes from SCIENCE and other ongoing trials to determine whether these early pathological responses translate into meaningful long-term benefit. In addition, the NEXUS-1 trial demonstrated the potential efficacy of a conversion strategy using sequential ICI following CRT in patients with unresectable locally advanced ESCC, highlighting the clinical value of converting initially unresectable disease to resectable status.

Definitive immunoradiotherapy in locally advanced ESCC

The NOBEL trial was a multicenter single-arm phase II study conducted in Japan that evaluated nivolumab, an anti-PD-1 antibody, in combination with dCRT for locally advanced ESCC (59). A total of 41 patients were evaluated, including 25 (61%) with resectable disease and 16 (39%) with unresectable disease. Patients received cisplatin and 5-fluorouracil (FP) plus nivolumab with concurrent RT (50.4 Gy in 28 fractions), followed by two additional cycles of FP plus nivolumab, and then maintenance nivolumab for up to 1 year. The regimen was feasible, meeting the predefined safety endpoint with grade ≥3 pneumonitis observed in only 4.8%. The overall complete response (CR) rate was 73.2%, with 84.0% in the resectable cohort and 56.3% in the unresectable cohort. One-year OS was 100% and 81.3% in the resectable and unresectable groups, respectively. Importantly, comprehensive gene expression profiling of pretreatment biopsy specimens focusing on 51 immune-related genes identified two intrinsic immune subtypes. The “high-active” subtype, characterized by elevated expression of cytotoxic T-cell- and interferon-related genes, achieved a 100% (4/4) CR rate, compared with 70.3% (26/37) in the “moderate-active” subtype. These findings support the concept that immune-active signatures correlate with sensitivity to CRT and ICI and suggest that the “high-active” subtype may serve as a predictive biomarker for response to immunoradiotherapy.

The EC-CRT-001 trial was a single-arm phase II study conducted in China, enrolling 42 patients with unresectable locally advanced ESCC (stage I–IVA) (60,61). Patients received dCRT consisting of weekly paclitaxel and cisplatin plus thoracic RT (50.4 Gy in 28 fractions), combined with toripalimab, an anti-PD-1 antibody, followed by consolidation toripalimab for up to 1 year. The primary endpoint, clinical CR (cCR) rate at 3 months post-CRT, was not met, with a rate of 62% falling short of the prespecified 64%. With a median follow-up of 44.3 months, the 3-year OS and PFS rates were 44.8% and 35.7%, respectively, with cCR attainment emerging as the sole independent prognostic factor. Although the primary endpoint for cCR was not met, the overall outcomes were relatively favorable. However, the clinical significance of cCR in the setting of RT and ICI remains unclear at present and should be interpreted with caution. In addition to clinical outcomes, EC-CRT-001 incorporated translational analyses. Baseline PD-L1 expression showed no significant correlation with response or survival. By contrast, a high intratumoral CD8⁺ T-cell density was strongly associated with improved cCR (85% vs. 35%) and 1-year PFS (75% vs. 30%). Moreover, MCL1 amplification emerged as a resistance biomarker, being significantly associated with worse OS and PFS. Overall, EC-CRT-001 highlights both the clinical potential and the biological challenges of integrating PD-1 blockade with dCRT in unresectable ESCC, while also providing important translational insights into biomarkers such as CD8⁺ T-cell density and MCL1 amplification.

In Japan, the multicenter single-arm phase II TENERGY (EPOC1802) trial evaluated atezolizumab, an anti-PD-L1 antibody, following dCRT in patients with unresectable locally advanced ESCC, predominantly cT4b and stage IVA–IVB disease (51). The primary cohort comprised 40 patients, and eligible patients received FP with 60 Gy/30 fractions of RT without elective nodal irradiation, followed by up to 1 year of atezolizumab. The primary endpoint, confirmed cCR rate, was achieved with 42.1%, surpassing the prespecified threshold, and the median and 12-month OS were 31.0 months and 65.8%, respectively. Importantly, comprehensive translational research was incorporated. Serial biopsies and blood sampling demonstrated that dCRT enhanced innate and adaptive immune responses via the cGAS-STING and RIG-I pathways, upregulated PD-L1 in tumor and antigen-presenting cells, and increased effector T-cell activity, supporting the rationale for sequential ICI administration after RT. Notably, activation of the TIGIT pathway was suggested as a potential resistance mechanism after dCRT with maintenance atezolizumab, indicating that other immunosuppressive circuits may predominate. Based on these observations, it was hypothesized that dual immune checkpoint blockade of TIGIT and PD-L1 might overcome adaptive resistance, leading to its clinical evaluation in this setting.

The global randomized double-blind placebo-controlled phase III SKYSCRAPER-07 trial investigated the efficacy of dual blockade of TIGIT and PD-L1 following dCRT in patients with unresectable locally advanced ESCC who had no disease progression after dCRT (n=760) (35). The study evaluated tiragolumab, an anti-TIGIT antibody, plus atezolizumab, atezolizumab plus placebo, or placebo alone, administered after dCRT. The trial did not meet its primary endpoint, as the tiragolumab plus atezolizumab arm failed to improve investigator-assessed PFS or OS vs. placebo alone [PFS: HR =0.82, 95% confidence interval (CI): 0.65–1.03, P=0.0947; OS: HR =0.91, 95% CI: 0.70–1.18, P=0.4772]. However, exploratory analyses suggested a potential efficacy in patients with high PD-L1 expression, particularly those with tumor area positivity ≥10%, who showed improved outcomes with tiragolumab plus atezolizumab compared with placebo alone (PFS: HR =0.69, 95% CI: 0.47–1.01; OS: HR =0.62, 95% CI: 0.40–0.94). Notably, atezolizumab monotherapy demonstrated clinically meaningful improvements in both PFS and OS compared with placebo alone (PFS: HR =0.74, 95% CI: 0.58–0.93, P=0.0113; OS: HR =0.69, 95% CI: 0.52–0.91, P=0.0085), although formal statistical testing was not conducted due to the hierarchical testing procedure. The addition of tiragolumab did not provide incremental benefit overall and was associated with higher toxicity and reduced treatment delivery: the tiragolumab plus atezolizumab arm experienced a 10% higher incidence of treatment-related adverse events and a 7.4% increase in adverse events of special interest, and patients in this arm received a median of five fewer cycles of tiragolumab plus atezolizumab compared with those receiving atezolizumab monotherapy, which may have attenuated the therapeutic efficacy of the dual checkpoint blockade.

Both the NOBEL and EC-CRT-001 trials demonstrated the clinical potential of concurrent dCRT and ICI, particularly in achieving favorable cCR rates. Building on the promising results of the TENERGY trial, the SKYSCRAPER-07 study was highly anticipated; although the primary endpoint of dual blockade was not met, the potential signal observed in the atezolizumab monotherapy arm is clinically significant. This finding provides a crucial proof-of-concept that sequential ICI administration following dCRT is a viable strategy in ESCC.

Immunoradiotherapy in metastatic ESCC

RT and ICI combination strategies are also being explored in metastatic ESCC, with several recent phase II studies in oligometastatic or unresectable stage IV disease reporting encouraging response rates and manageable safety profiles (62-64,66), as summarized in Table 4.

Current challenges and evolving landscape of immunoradiotherapy

In ESCC, the combination of concurrent RT and ICI has shown promising results in prior studies; however, long-term survival outcomes from phase III trials have not yet been reported. In other malignancies, among phase III trials of concurrent RT and ICI, only the KEYNOTE-A18 trial in cervical cancer has demonstrated clinical benefit (29), whereas several other phase III studies have reported negative results (17,20-22,30,32,33).

In lung cancer, while the PACIFIC trial established the benefit of sequential ICI administration after RT (16), the PACIFIC-2 trial evaluating concurrent ICI administration yielded negative results (17), prompting further discussion. One consideration is that with conventional fractionated RT, the prolonged treatment period results in extended depletion of circulating and nodal lymphocytes (67-72), which may limit the efficacy of concurrently administered ICI (73).

Another challenge in concurrent strategies concerns the irradiated field. Prophylactic irradiation with wide treatment fields may exacerbate lymphocyte depletion, thereby hindering the efficacy of ICI (73). In line with this concern, in head and neck cancer, two phase III trials evaluating concurrent RT and ICI were negative, and it has been suggested that extensive prophylactic irradiation might have compromised treatment efficacy (21,22). Supporting this notion, preclinical studies in head and neck cancer have indicated advantages of omitting elective nodal irradiation in the concurrent setting (74-77).

Both prolonged treatment duration and extensive irradiated fields ultimately lead to lymphocyte depletion, suggesting that conventional fractionated RT with extended courses and wide prophylactic fields may be suboptimal when combined concurrently with ICI. Indeed, across multiple malignancies, ICIs have demonstrated efficacy when administered sequentially after RT in accumulating phase III trials (18,19,27,31), supporting this approach as the current standard (78-80). This sequential benefit may be attributed to the timing of ICI administration, which coincides with lymphocyte recovery after RT-induced depletion. Alternatively, for concurrent ICI administration, preclinical data and the randomized phase II iSABR trial in lung cancer suggest that hypo-fractionated RT regimens such as stereotactic body RT (SBRT), delivering a higher dose per fraction over a shorter treatment course, may enhance synergy by minimizing the exposure of circulating immune cells to radiation (81,82). However, in luminal organs such as the esophagus, the clinical application of SBRT is expected to be challenging due to the risk of severe toxicity (83).

Taken together, when conventional fractionated RT is employed—with or without prophylactic irradiation—sequential ICI administration following RT appears to yield superior efficacy. Conversely, hypo-fractionated regimens such as SBRT, which deliver higher doses per fraction over a shorter course, may provide an opportunity for enhanced therapeutic synergy even in the concurrent setting.

Emerging directions and future perspectives of immunoradiotherapy

The content so far has summarized completed clinical trials, whereas this section focuses on ongoing studies currently investigating RT and ICI combination strategies.

Ongoing trials of preoperative immunoradiotherapy in locally advanced ESCC

PALACE-2 (NCT04435197) is a prospective multicenter single-arm phase II study (n=143) evaluating preoperative pembrolizumab plus CRT in resectable locally advanced ESCC. Primary endpoint is pCR rate (58). NEOCRTEC-2101 (NCT05357846) is a Chinese multicenter randomized phase III trial (n=422) evaluating neoadjuvant CRT with or without sintilimab followed by surgery in resectable locally advanced ESCC. Primary endpoint is OS.

In the context of concurrent RT and ICI, strategies to increase the dose per fraction and shorten the irradiation period, while omitting prophylactic RT, are being explored in ESCC in Japan. The phase II PALADIN trial is a single-institution, single-arm study currently ongoing for patients with unresectable locally advanced ESCC (jRCT1031250183). Eligible patients include those with cT3br–4bNanyM0 (Japanese Classification of Esophageal Cancer, 12^th edition) disease without distant metastasis, but supraclavicular lymph node metastasis is permitted. This trial is evaluating the efficacy and safety of an induction treatment consisting of pembrolizumab plus FP combined with short-course RT (25 Gy in 5 fractions) without elective nodal irradiation, followed by conversion surgery. The primary endpoint is 2-year OS. One of the major concerns with combining RT and ICI is the increased risk of interstitial pneumonitis (IP). Previous studies have suggested that reducing the total radiation dose may lower the incidence of IP in this setting (84-86). By adopting short-course RT, the PALADIN trial aims not only to enhance synergy with concurrent ICI but also to decrease the risk of IP. Moreover, since surgery after high-dose radiation is known to carry substantial risks in unresectable locally advanced ESCC (87,88), dose reduction in this setting is also anticipated to improve surgical safety. Enrollment has begun, and the results are eagerly awaited.

In the SANO trial, patients with resectable locally advanced esophageal cancer who achieved a cCR after neoadjuvant CRT were assigned to either active surveillance (AS) or standard esophagectomy, and AS was shown to be non-inferior to surgery (89). Based on this result, an AS strategy combined with RT and ICI is being investigated. The ongoing non-randomized, single-arm phase II SANO-3 trial (NCT05491616) is evaluating maintenance nivolumab during AS in esophageal cancer patients achieving cCR after neoadjuvant CRT. Similar to the CheckMate 577 trial, sequential nivolumab is expected to improve outcomes in this population.

The pCR rate after neoadjuvant CRT was higher in SCC (49%) compared with adenocarcinoma (23%) (4), and some have suggested that AS should therefore be considered primarily in SCC (89). Based on this concept, the randomized phase II WATCHER trial (NCT05507411) is evaluating resectable locally advanced ESCC patients (n=100) who achieve cCR after neoadjuvant CRT combined with camrelizumab, randomizing them to either AS or standard surgery. In both arms, patients receive maintenance camrelizumab. The primary endpoint is the 1-year DFS in the AS group. In parallel, the randomized phase III PALACE-3 trial (NCT06339060) is evaluating patients with resectable locally advanced ESCC, randomizing them to either AS after neoadjuvant CRT combined with camrelizumab or standard radical surgery after neoadjuvant CRT. The primary endpoint is the 3-year OS.

With the growing interest in AS as an organ-preserving strategy in esophageal cancer, recent meta-analyses reported higher pCR rates of CRT and ICI compared with CRT alone (90,91), suggesting that the addition of ICI may increase the proportion of patients eligible for AS. Consistent with this concept, the WATCHER and PALACE-3 trials are investigating CRT and ICI as a strategy to expand AS eligibility by increasing conversion to cCR. In contrast, the SANO-3 trial is evaluating maintenance ICI after CRT to reduce recurrence during AS. Although SANO-3 focuses on the maintenance approach, accumulating evidence indicates that sequential ICI after RT may further improve outcomes. If supported by prospective data, this strategy would warrant evaluation in a phase III setting.

Ongoing trials of definitive immunoradiotherapy in locally advanced ESCC

KEYNOTE-975 (NCT04210115) is a multinational randomized phase III trial (n=600) evaluating pembrolizumab plus dCRT vs. placebo plus dCRT in unresectable locally advanced esophageal carcinoma. Primary endpoints are OS and EFS (36). KUNLUN (NCT04550260) is an international randomized phase III trial (n=600) evaluating durvalumab, an anti-PD-L1 antibody, plus dCRT followed by durvalumab maintenance vs. placebo plus dCRT in unresectable locally advanced ESCC. The co-primary endpoint is PFS in all randomized patients and in patients with PD-L1-high tumors (37). RATIONALE-311 (NCT03957590) is a Chinese randomized phase III trial (n=366) evaluating tislelizumab plus dCRT vs. placebo plus dCRT in unresectable locally advanced ESCC. Primary endpoint is PFS (38). ESCORT-CRT (NCT04426955) is a Chinese randomized phase III trial (n=396) evaluating camrelizumab, an anti-PD-1 antibody, plus dCRT vs. placebo plus dCRT in unresectable locally advanced ESCC. Primary endpoint is PFS.

Four large-scale randomized phase III trials are currently investigating the concurrent use of ICI with dCRT in unresectable locally advanced ESCC. Among them, the KUNLUN trial includes stratified analyses in PD-L1-high populations, which may provide insights into the clinical utility of biomarker-based patient selection in this setting.

Ongoing trials of immunoradiotherapy in metastatic ESCC

Several randomized phase II trials are currently ongoing to define the role of RT in combination with ICI for advanced or oligometastatic ESCC (NCT05183958, NCT05512520, and NCT05628610), as summarized in Table 4.

A randomized phase II JCOG2311 trial (jRCT1031240461) is evaluating sequential administration of nivolumab plus ipilimumab with or without RT in patients with unresectable or recurrent esophageal cancer. Patients in the experimental arm receive RT (24 Gy in3 fractions or 25 Gy in 5 fractions) followed by nivolumab plus ipilimumab, while the control arm receives nivolumab plus ipilimumab alone (65). It aims to identify predictive and prognostic biomarkers by analyzing immune cell phenotypes and cytokine profiles in peripheral blood mononuclear cells collected at multiple time points before and during treatment. Integrated clinical and immunologic data will be analyzed to explore biomarkers associated with treatment response and outcomes.

The combination of RT and ICI has expanded beyond oligometastatic disease to include stage IVB cases. In the JCOG2311 trial, sequential dual ICI following RT is being explored. By combining RT with dual ICIs, a stronger synergistic effect is anticipated, and this study is expected to clarify whether sequential ICI therapy can also demonstrate meaningful efficacy in patients with stage IVB disease.

Next-generation translational research to refine patient selection for immunoradiotherapy in ESCC

Recent large-scale genomic and multi-omics studies have highlighted the substantial molecular heterogeneity of ESCC, identifying clinically relevant subtypes beyond histology (92,93). In particular, alterations in the NRF2 oxidative stress response pathway (e.g., NFE2L2/KEAP1/CUL3) define a major molecular subset and have been associated with resistance to CRT. Integrated profiling has also proposed immune-related gene expression subtypes, some of which may predict differential sensitivity to immune checkpoint blockade. However, the clinical implementation of transcriptomic biomarkers requires robust standardization of gene expression platforms across cohorts.

Building on the translational insights from the TENERGY trial, initial biological hypotheses for dCRT followed by ICI in ESCC have begun to emerge (51). Bulk RNA sequencing revealed that dCRT activates innate immune sensing pathways, enhances interferon signaling, and reshapes the tumor immune microenvironment, while resistance was associated with epithelial-mesenchymal transition, TGF-β signaling, regulatory T-cell activation, and IL-1-driven inflammation. These findings provided important mechanistic hypotheses but also highlighted the intrinsic limitations of bulk transcriptomic analyses.

Bulk RNA sequencing averages signals across heterogeneous cell populations and lacks spatial context, both of which are critical in immunoradiotherapy, where radiation induces highly localized and cell type-specific immune remodeling (94). To improve predictive accuracy and patient stratification, higher-resolution translational platforms are required. Single-cell RNA sequencing enables detailed characterization of immune and stromal cell states that govern treatment response (95). In particular, it allows identification of CD8⁺ T-cell subsets with reinvigoration potential, suppressive regulatory T-cell populations expressing CTLA-4 or TIGIT, and radiation-induced inflammatory myeloid and fibroblast programs, which have already been described in ESCC and in the context of RT-induced immune remodeling (96-98). These analyses provide mechanistic insight into response and resistance and support rational combinatorial strategies beyond PD-1/PD-L1 blockade.

Spatial transcriptomic technologies further refine this understanding by preserving tissue architecture. By mapping immune cell localization relative to tumor cells and irradiated regions, spatial profiling can reveal suppressive niches, immune exclusion, and spatially restricted immune activation that cannot be inferred from dissociated analyses (99-101). Given the central role of dose distribution and field design in RT, spatial approaches are particularly relevant for immunoradiotherapy.

Plasma proteomics complements tissue-based analyses by capturing systemic immune and inflammatory responses (102,103). Circulating protein signatures reflecting interferon activation or IL-1-associated inflammation may serve as minimally invasive indicators of effective antitumor immunity or emerging resistance during treatment (104).

Together, integration of single-cell, spatial transcriptomic, and plasma proteomic analyses offers a promising strategy to translate biological insights from trials such as TENERGY into more precise patient selection and rational trial design. These next-generation translational approaches may be essential to fully realize the potential of immunoradiotherapy in ESCC.

Conclusions

Inspired by the success of the CheckMate 577 trial, which established the efficacy of sequential ICI therapy, the combination of RT and ICI has rapidly gained momentum in locally advanced and metastatic ESCC. In the TENERGY trial, activation of the TIGIT pathway was observed in patients who failed to benefit from sequential ICI after dCRT, suggesting resistance mediated by TIGIT signaling and providing a rationale for dual blockade with TIGIT and PD-L1. The phase III SKYSCRAPER-07 trial was expected to answer this question, but unfortunately failed to demonstrate the efficacy of dual ICI therapy after dCRT. However, this does not signify the end of immunoradiotherapy in ESCC. Rather, the robust efficacy of sequential ICI monotherapy, which has been consistently demonstrated across various malignancies, further reinforces its role.

Across tumor types, the strategy of concurrent RT and ICI has shown limited success, yet the phase II NOBEL and phase III SCIENCE trials demonstrated encouraging pCR improvements in ESCC. At present, several phase III trials are ongoing to evaluate concurrent RT and ICI in unresectable locally advanced esophageal cancer, and their results are keenly awaited to shape the next era of immunoradiotherapy. In particular, the KUNLUN trial has attracted attention for including stratified analyses in PD-L1-high populations, which may provide insights into the clinical utility of biomarker-based patient selection in this setting. Furthermore, trials are also underway to evaluate AS following CRT and ICI, reflecting the growing interest in the nonoperative management of esophageal cancer.

In this context, future progress in immunoradiotherapy for ESCC will critically depend on the integration of next-generation translational research, including single-cell, spatial transcriptomic, and circulating biomarker analyses, to refine patient selection, elucidate mechanisms of resistance, and guide biologically informed trial design.

The development of treatment strategies integrating RT and ICI in ESCC is still evolving, and the door remains open for further breakthroughs.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Ken Kato) for the series “Multimodal Approach and Clinical Application for Esophageal Cancer” published in Annals of Esophagus. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aoe.amegroups.com/article/view/10.21037/aoe-2025-1-46/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-2025-1-46/coif). The series “Multimodal Approach and Clinical Application for Esophageal Cancer” was commissioned by the editorial office without any funding or sponsorship. D.K. has received honoraria from Sysmex, Seagen, Guardant Health, Takeda, Chugai, Lilly, MSD, Ono, Taiho, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Eisai, and Merck Biopharma, and research funding from Ono, MSD, Novartis, Servier, Janssen, IQVIA, Syneos Health, Cimic, and Cimicshiftzero outside the submitted work. H.B. has received consulting fees from AMCA. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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