Neoadjuvant immunochemoradiotherapy in esophageal squamous cell carcinoma: an updated narrative review

Introduction

Background

According to the GLOBOCAN 2022 estimates, esophageal cancer ranks as the 11th most commonly diagnosed cancer and the seventh leading cause of cancer-related death worldwide, with approximately 511,000 new cases and 445,000 deaths reported that year (1). The incidence of esophageal cancer exhibits marked geographical heterogeneity. In particular, China bears a disproportionate burden, accounting for approximately half of all global cases and representing the region of highest incidence. Notably, men aged 50 years and older in China experience the highest incidence rates worldwide. The age-standardized incidence rate in China (11–14 per 100,000) is substantially higher than rates observed in Western populations (e.g., 3.4 per 100,000 in the United States) (2,3).

The prognosis for resectable, locally advanced esophageal squamous cell carcinoma (ESCC) remains poor despite diagnostic and therapeutic advances. With surgery alone, recurrence is common, and five-year survival rates are limited to 20–40% (4). The need to improve survival in locally advanced disease has driven the adoption of neoadjuvant therapy, which aims to downstage the primary tumor, eliminate micrometastases, and facilitate radical resection. A cornerstone of recent progress is immunotherapy, notably programmed cell death protein 1 (PD-1) and its ligand (PD-L1) inhibitors, which have reshaped the therapeutic landscape. Landmark trials have confirmed significant survival benefits with agents such as nivolumab in advanced metastatic ESCC, supporting their integration into earlier lines of therapy (5).

The combination of immunotherapy with conventional neoadjuvant chemoradiotherapy (nCRT) leverages the immune-stimulating effects of radiotherapy and chemotherapy, triggering immunogenic cell death and modulating the tumor immune microenvironment, to enhance immune checkpoint inhibitor efficacy, providing a robust theoretical foundation for this integrated approach (6).

Although neoadjuvant immunotherapy in esophageal cancer has attracted considerable attention, with several reviews summarizing it from different perspectives, this review provides an updated perspective on this rapidly developing field. In contrast to Ghalehtaki et al. (7), which specifically addressed optimal timing for combining immune checkpoint inhibitors with nCRT, this review integrates a more comprehensive evidence system. It not only summarizes concurrent treatment approaches but also includes studies exploring different treatment sequences (such as sequential therapy in the CRISEC trial) and expands discussion to application prospects in locally advanced unresectable and advanced metastatic ESCC, constructing a complete evidence chain from surgical resectability to transformation to advanced first-line treatment. Compared with Li et al. (8), which systematically described neoadjuvant immunotherapy rationale and summarized early evidence up to 2022, this review includes updated data through 2025, such as preliminary SCIENCE trial results and the NEXUS-1 study, confirming earlier findings and revealing pathological complete response (pCR) rates up to 60%. Unlike Yu et al. (9), which compared neoadjuvant immunotherapy efficacy in ESCC and adenocarcinoma and explored tumor immune microenvironment mechanisms, this review also analyzes real-world safety challenges of triple therapy (such as esophageal fistula risk) and explores biomarkers [circulating tumor DNA (ctDNA), CD8⁺ T-cell density], aiming to provide more practical guidance for individualized precision treatment.

Rationale and knowledge gap

While numerous trials have demonstrated efficacy, critical questions remain. The optimal sequencing of modalities—concurrent versus sequential induction—is debated. Furthermore, the differential benefit across disease stages (resectable, unresectable, metastatic) and the role of biomarkers require clarification. This review addresses these gaps by synthesizing current evidence and providing a stage-specific, biomarker-informed framework.

Objective

This narrative review examines the current landscape of neoadjuvant immunotherapy combined with chemoradiation in ESCC, synthesizing clinical trial data to elucidate mechanisms, evaluate efficacy (particularly pCR and survival) and safety, discuss challenges and future directions, and provide a reference for clinical practice and research.

Despite encouraging results from studies like PALACE-1 and SCIENCE, critical questions remain regarding optimal immunotherapy integration with chemoradiotherapy. Sequencing of these modalities, whether given concurrently, sequentially (induction followed by chemoradiotherapy), or as consolidation or maintenance therapy, is intensely debated (10). Furthermore, while combination therapy shows promise in operable disease, its role in definitively managing unresectable locally advanced ESCC is an area of urgent clinical need (11). This review therefore aims to analyze the evolving landscape of neoadjuvant and definitive immunochemoradiotherapy, with specific focus on treatment sequencing, the emerging paradigm of induction therapy, and the critical role of maintenance strategies in optimizing long-term outcomes for ESCC patients across different disease stages. We present this article in accordance with the Narrative Review reporting checklist (available at https://aoe.amegroups.com/article/view/10.21037/aoe-2026-1-0009/rc).

Methods

Information sources and search strategy

A literature search of PubMed and CNKI was conducted on September 1, 2025 using MeSH and free-text terms. Key search terms included “esophageal squamous cell carcinoma”, “neoadjuvant therapy”, “immune checkpoint inhibitors”, and “chemoradiotherapy”, combined with “AND”. The search covered records from January 2000 to March 2026.

We included prospective or retrospective clinical studies of neoadjuvant immunochemoradiotherapy in patients with ESCC. Case reports, preclinical studies, and articles with incomplete data were excluded. Data on study design, patient characteristics, treatment, efficacy (pCR, survival), and safety were extracted. Given the study heterogeneity, a narrative synthesis was performed. The search strategy is detailed in Table 1.

Mechanistic basis

The rationale for combining neoadjuvant immunotherapy with chemoradiotherapy rests on a synergistic biological foundation that enables a self-sustaining “prime-expand-sustain” antitumor immune cycle. This synergy is achieved through three key mechanistic interactions.

First, chemoradiation primes a tumor-specific immune response by inducing immunogenic cell death. This process leads to the release of damage-associated molecular patterns (DAMPs) from therapy-exposed tumor cells. Key among these, calreticulin exposure on the cell surface serves as a critical “eat-me” signal, facilitating uptake by dendritic cells. These dendritic cells subsequently process and present tumor-associated antigens via major histocompatibility complex molecules, thereby activating adaptive immunity. Concurrently, DAMPs such as HMGB1 and ATP act on dendritic cells (DCs) to stimulate the secretion of inflammatory cytokines, including IL-1β, which in turn promotes DC maturation and enhances T-cell activation (12-14).

Second, despite initiating an immune response, radiotherapy and chemotherapy also upregulate immunosuppressive signals within the tumor microenvironment, most notably PD-L1 expression. This therapy-induced upregulation of PD-L1 then engages PD-1 receptors on activated T cells, leading to T-cell exhaustion or apoptosis and thereby limiting the antitumor immune response (15-17).

Third, PD-1/PD-L1 inhibitors intervene precisely at this point by blocking this key inhibitory axis (15). This releases the brakes on the primed T cells (18), enabling the tumor-specific clones expanded by chemoradiation to fully proliferate, differentiate, and exert sustained cytotoxic effects (19,20).

Finally, the combined regimen reshapes the systemic antitumor immune landscape. This approach not only converts the local tumor microenvironment from immunosuppressive to immunostimulatory, characterized by increased effector T-cell infiltration and function alongside relative regulatory T-cell decline, but also induces systemic immune activation. Critically, this systemic activation enables immune cells to recognize and eliminate micrometastatic deposits distant from the primary site, mediating the abscopal effect. The generation of this systemic, antigen-specific immune response is thus a pivotal mechanism for achieving durable survival benefits with neoadjuvant immunochemoradiotherapy (6,19).

Ultimately, the combination of neoadjuvant immunotherapy with chemoradiotherapy constitutes a rational strategy for improving outcomes through multifaceted biological cooperation. Synergistically rather than additively, it fosters a dynamic cycle encompassing antigen release and presentation, reversal of T-cell inhibition, clonal expansion of tumor-specific lymphocytes, and sustained modification of the immune microenvironment, as illustrated in Figure 1.

Figure 1 Mechanistic basis of neoadjuvant immunochemoradiotherapy in ESCC. CRT, chemoradiotherapy; DC, dendritic cell; ESCC, esophageal squamous cell carcinoma; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; Teff, effector T cell; Treg, regulatory T cell.

Locally advanced operable ESCC

The PALACE-1 trial pioneered the investigation of neoadjuvant immunotherapy combined with chemoradiotherapy (21). In this phase II study, patients received pembrolizumab plus concurrent carboplatin and paclitaxel, followed by surgery. Among 20 enrolled patients, 18 (90%) underwent resection, with R0 resection achieved in 17 (94% of those resected). The major pathological response (MPR) rate among resected patients was 89% (16/18). Notably, no disease recurrence was reported in patients who underwent curative resection.

A comparative study further supported this approach (22). Among patients receiving neoadjuvant therapy followed by esophagectomy, those treated with ICIs plus nCRT achieved a significantly higher primary tumor pCR rate than those receiving ICIs plus chemotherapy alone (52.9% vs. 21.6%; P=0.03). Minimally invasive surgery rates were high in both groups (94.1% vs. 89.2%), with comparable postoperative complications. Hematologic toxicity was the most common adverse event (AE), occurring in 100% of the ICI-nCRT group and 91.3% of the ICI-chemotherapy group. Grade ≥3 AEs in the ICI-nCRT group included esophagitis (18.2%) and pneumonia (4.5%).

Subsequently, multiple studies further validated and refined this combined approach. The phase II NCT04437212 trial enrolled 21 patients with resectable thoracic ESCC, administering nCRT (41.4 Gy radiotherapy with weekly paclitaxel/cisplatin) plus two cycles of toripalimab, followed by four adjuvant cycles post-surgery (23). This approach yielded a pCR rate of 47.4% and MPR rate of 78.9%, ranking among the highest pCR rates reported. The safety profile was manageable, with grade ≥3 treatment-related AEs being predominantly lymphopenia; immune-related AEs were mostly mild to moderate.

The NEOCRTEC1901 trial evaluated toripalimab combined with concurrent chemoradiotherapy (paclitaxel, cisplatin, and 44 Gy radiotherapy) in 40 patients (24). The reported pCR rate was 50%, which did not reach statistical significance compared to historical controls (P=0.19). However, early survival outcomes appeared promising, with 1-year overall survival (OS) and progression-free survival (PFS) rates potentially exceeding 95%, and a 2-year OS rate of 81.5%. The regimen demonstrated a manageable safety profile, with grade ≥3 AEs in 20% of patients. Close monitoring for postoperative complications, including anastomotic leakage, is recommended.

Preliminary results from the SCIENCE trial, presented in a recent conference report (25,26), demonstrate the efficacy of integrating immunotherapy with concurrent chemoradiotherapy. Patients were randomized to receive sintilimab plus chemotherapy, sintilimab plus concurrent chemoradiotherapy, or concurrent chemoradiotherapy alone. pCR rate was highest in the sintilimab plus concurrent chemoradiotherapy arm at 60%, compared to 13% with sintilimab plus chemotherapy and 47.3% with concurrent chemoradiotherapy alone.

Not all trials met their primary endpoints. The CRISEC trial investigated sequential tislelizumab following nCRT (27). The observed pCR rate was 37.5%, falling short of the prespecified target of 52.7%. A post hoc analysis suggested that differences in radiation target volume may have contributed to this outcome. Despite not meeting the pCR endpoint, the regimen yielded encouraging survival outcomes, with 2-year OS and PFS rates of 83.3% and 79.2%, respectively. Notably, patients achieving pCR had a 2-year OS of 100%. Treatment was generally well-tolerated. However, a notable risk of fatal hemorrhage due to tumor invasion of major vessels was identified, warranting close monitoring.

Locally advanced unresectable ESCC

For patients with initially unresectable or borderline resectable tumors, neoadjuvant immunochemoradiotherapy offers a strategy to facilitate conversion surgery. The NCT05355368 trial evaluated a regimen of nCRT (carboplatin/paclitaxel) combined with dual immune checkpoint blockade (camrelizumab plus nimotuzumab) in this population (28). Reported pCR and MPR rates were 37% and 53%, respectively. At a median follow-up of 18.5 months, the 1-year OS and PFS rates were 80% and 67%, respectively.

The NEXUS-1 study investigated a three-phase conversion strategy for patients with locally advanced, initially unresectable ESCC (29). This approach first utilized concurrent chemoradiotherapy for tumor downstaging. Patients without progression then received tislelizumab combined with chemotherapy to amplify the immune response. Finally, surgical resection was attempted in those achieving sufficient downstaging. Results demonstrated a successful conversion-to-surgery rate of 66.7%, with an R0 resection rate of 95.2% among those undergoing surgery. Moreover, pCR and MPR rates reached 65% and 90%, respectively, indicating a potent antitumor effect. The regimen was associated with manageable toxicity, supporting further investigation of this sequential, multimodality approach.

In summary, neoadjuvant immunotherapy combined with concurrent chemoradiotherapy demonstrates considerable promise in the management of locally advanced ESCC. As evidenced by consistently improved pCR rates ranging from 37% to 60% across studies. Notably, in the SCIENCE trial, the addition of sintilimab to chemoradiotherapy elevated the pCR rate to 60%, a result significantly superior to comparator arms and robustly supporting the synergistic potential of this combination.

While mature long-term survival data are still awaited, early outcomes are encouraging, with reported 1-year OS and PFS rates reaching approximately 80% and 67%, respectively. Collectively, evidence indicates that this integrated strategy not only induces profound pathological remission but also holds promise for durable survival benefits.

Systemic first-line therapy for metastatic or recurrent ESCC

The ChiCTR2100046715 trial evaluated toripalimab plus concurrent chemoradiotherapy (paclitaxel/carboplatin) in advanced ESCC (30). In 33 evaluable patients, the objective response rate was 45.5%, the disease control rate was 57.6%, and the median duration of response was 11.5 months. Median PFS was 9.8 months (1-year PFS rate 41.9%), and the 1-year OS rate was 69.7%.

A multicenter study by Liu et al. further investigated consolidative radiotherapy in this setting (31). The study included 343 patients with previously untreated, metastatic ESCC limited to non-regional lymph nodes. Using propensity score matching, the authors compared first-line PD-1 inhibitor plus chemotherapy with or without radiotherapy. The radiotherapy consolidation group showed significantly superior outcomes: median OS was 22.3 vs. 14.9 months [hazard ratio (HR) 0.51], median PFS was 14.0 vs. 6.1 months (HR 0.57), and higher objective response rate (64.8% vs. 36.0%) and disease control rate (92.0% vs. 76.8%).

A retrospective analysis by Hou et al. involving 141 patients with advanced ESCC receiving first-line immunotherapy further supports this approach (32). Among them, 75 received consolidative radiotherapy. After a median follow-up of 31.7 months, patients receiving radiotherapy had significantly longer median PFS (16.2 vs. 9.3 months; HR 0.65) and OS (25.2 vs. 14.6 months; HR 0.57). Multivariable analysis confirmed radiotherapy as an independent favorable prognostic factor.

Collectively, current evidence indicates that adding radiotherapy to immunochemotherapy can improve response rates and confer a significant survival benefit in selected patients with advanced ESCC, particularly those with oligometastatic disease. To translate this promise into standard practice, future efforts should focus on conducting phase III trials to establish unified technical standards and on exploring individualized radiotherapy strategies guided by predictive biomarkers.

Safety

Data from multiple clinical trials indicate that the safety profile of neoadjuvant immunotherapy combined with chemoradiotherapy in locally advanced ESCC is generally manageable, and perioperative management pathways are becoming established.

Treatment-related AEs are highly prevalent, though most are grade 1–2. The most common toxicities are hematologic. Lymphopenia and leukopenia occur in the vast majority of patients, while neutropenia and anemia are also common, with reported incidences of 30–80% across studies (21,24,26,28).

Immune-related AEs occur in approximately 20–32% of patients (24,28), most commonly manifesting as thyroid dysfunction (e.g., hypothyroidism), rash, fatigue, or elevated transaminases. Over 90% of these are grade 1–2.

Grade ≥3 treatment-related AE incidence varies across trials (20–71.4%), necessitating close monitoring. Grade 3–4 lymphopenia is the most frequent severe event, with an incidence as high as 66–92%. Although most toxicities are manageable, serious complications, including the most critical and potentially fatal event of esophageal hemorrhage, have been reported (one grade 5 event each in the NEOCRTEC1901 and PALACE-1 trials). Other notable serious events include pneumonia (radiation- or immune-mediated), severe esophagitis, and hepatotoxicity.

The integration of immunotherapy did not compromise surgical feasibility. The intervals from the completion of neoadjuvant therapy to surgery (56–74.5 days) and from the last immunotherapy dose to surgery (27.5–35 days) afforded a sufficient window to manage potential immune-related AEs without leading to unplanned surgical delays. Surgical outcomes were notable, with conversion-to-surgery rates of 86–100% and R0 resection rates of 94–100%. Critically, no perioperative mortality directly attributable to the treatment regimen was reported across the included studies (21,23,26,26-28).

In summary, although AEs are frequent, vigilant monitoring and proactive management render them largely manageable without compromising surgical feasibility.

Biomarker

Although neoadjuvant immunotherapy combined with chemoradiotherapy holds considerable promise, significant heterogeneity in therapeutic efficacy is observed in clinical practice. While some patients achieve pCR with potential for long-term cure, others derive limited benefit while still being exposed to the regimen’s toxicity. This pronounced heterogeneity underscores the urgent need for biologically informed, personalized treatment strategies.

Emerging evidence reveals response determinants encompass both pre-existing tumor features and therapy-induced tumor immune microenvironment remodeling. Wu et al. demonstrated a pretreatment three-gene signature (SERPINE1, LINC00592, PRKAG2-AS1) robustly predicted pCR to nCRT, indicating intrinsic tumor biology presets treatment sensitivity (33). Similarly, Huang et al. found mature tertiary lymphoid structures (TLS) in pretreatment biopsies independently predicted improved survival across neoadjuvant modalities, with immunotherapy promoting TLS maturation (34).

Beyond baseline factors, dynamic on-treatment changes critically shape outcomes. Han et al., using single-cell mass cytometry, revealed radiotherapy-containing regimens enhanced CD8⁺ T-cell infiltration and effector memory differentiation while depleting immunosuppressive CCR4⁺CCR6⁺ macrophages—a subset linked to treatment resistance (35). Crucially, failure to clear ctDNA during or after treatment identifies patients with dismal prognoses; Chen et al. reported post-treatment ctDNA positivity conferred significantly higher progression (HR 2.88) and death risks (HR 3.67), reflecting persistent therapy-resistant clones (36). Cheng et al. further found that low absolute lymphocyte count was associated with significantly worse PFS (13.5 months vs. not reached; P=0.026) and was an independent risk factor (37).

PD-L1 expression has shown inconsistent predictive value across settings. The GASTO 1071 trial and NEOCRTEC1901 both found no significant association between PD-L1 combined positive score and pCR or survival, despite numerically higher response rates in PD-L1-positive patients (24,38). In contrast, PD-L1 has demonstrated strong prognostic value in the setting of definitive chemoradiotherapy, underscoring the need for context-specific biomarker validation (22).

Peripheral blood biomarkers offer non-invasive, dynamic monitoring capability. Patients with undetectable ctDNA during treatment had significantly higher clinical complete response rates than those with detectable ctDNA (83% vs. 39%; P=0.008), and post-treatment ctDNA positivity was linked to significantly worse PFS (P=0.012) and OS (P=0.004) (36). Additionally, high PD-1⁺CD8⁺ T-cell density after chemoradiotherapy independently predicted complete response and favorable PFS, suggesting chemoradiotherapy modulates the immune landscape in ESCC (39).

Recent research from China has explored novel liquid biopsy approaches. A prospective study developed a circulating cell-free DNA methylation-based model that achieved remarkable accuracy in predicting MPR (86.3%) and pCR (90.9%) (40). This promising tool, if validated in larger cohorts, could revolutionize patient selection and enable truly personalized adaptive strategies.

Discussion

Consensus and controversies

Table 2 summarizes key clinical trials of neoadjuvant immunochemoradiotherapy in ESCC, and Figure 2 provides a visual overview of this integrated approach. Based on this evidence, several consensus points emerge from the evidence across multiple phase II trials. First, adding immunotherapy to nCRT consistently improves pCR rates (37–60%) across multiple phase II trials (21,23-26). Second, the combination is generally safe, with no compromise to surgical feasibility, as R0 resection rates of 94–100% are consistently reported (21,23,24,27,28). Third, mature TLS and dynamic ctDNA clearance are emerging as robust, context-independent prognostic biomarkers (34,36).

Figure 2 Visual summary of neoadjuvant immunochemoradiotherapy in ESCC across disease stages. ESCC, esophageal squamous cell carcinoma; ORR, objective response rate; OS, overall survival; pCR, pathological complete response; PD-1, programmed cell death protein 1; PFS, progression-free survival.

Key controversies remain unresolved. Optimal sequencing, whether concurrent (PALACE-1, SCIENCE) or sequential induction, is fiercely debated, with no head-to-head comparisons available. Concurrent administration maximizes pCR (up to 60% in SCIENCE) (26). However, sequential strategies utilizing induction chemoimmunotherapy prior to chemoradiotherapy followed by maintenance immunotherapy may offer distinct advantages, particularly for patients with unresectable disease. Chen et al. reported a phase II trial in 44 patients with locally advanced ESCC ineligible for surgery, achieving an objective response rate of 95.5%, median PFS 26 months, median OS 29 months, and 3-year OS of 42.0% with preserved quality of life (11). The Zhejiang Province Expert Consensus (2025) supports this approach, citing synergistic effects and manageable safety profiles observed in multiple phase II studies and the phase III ESCORT-NEO trial (40). The predictive value of PD-L1 expression is inconsistent across disease stages, as it is limited in the neoadjuvant setting (24,37,38) but prognostic in definitive chemoradiotherapy, underscoring the need for stage-specific biomarker validation. The risk of severe esophageal fistula (10–10.7% in heavily pretreated patients) remains a sobering reminder of the toxicity ceiling, demanding careful patient selection (22).

Stage-specific considerations and quantified benefit

Optimal immunochemoradiotherapy integration is fundamentally stage-dependent. In resectable disease, the primary goal is maximizing local response. Concurrent regimens yield pCR rates of 37–60%, a 2- to 3-fold increase over historical controls, supporting their use as preferred strategy (21,26). However, whether this translates to 5-year OS benefit awaits validation from ongoing phase III trials.

In unresectable disease, the goal shifts to enabling conversion surgery. Sequential strategies, either induction chemoimmunotherapy followed by chemoradiotherapy (11) or chemoradiotherapy followed by immunochemotherapy [NEXUS-1 (29)], achieve conversion rates of 66.7%, with pCR of 65% in resected specimens. This represents a paradigm shift for a population traditionally managed with definitive chemoradiotherapy alone, offering the greatest absolute benefit by altering disease trajectory.

In metastatic disease, radiotherapy serves a consolidative role. Adding radiotherapy to first-line immunochemotherapy prolongs median OS by 7.4–10.6 months (HR 0.51–0.57) (31,32). However, the evidence is exclusively retrospective, and optimal patient selection (likely oligometastatic) remains undefined.

Synthesizing these data, the therapeutic index appears highest in initially unresectable disease, where conversion to surgery fundamentally changes curative potential. The NEXUS-1 trial’s 65% pCR in converted patients is particularly striking (29). In resectable disease, the benefit is substantial but requires survival confirmation; in metastatic disease, the benefit is meaningful but evidence is weakest (Table 3).

Biomarkers and safety

Biomarker development remains critical. PD-L1 expression shows inconsistent predictive value across settings (24,37,38), while dynamic biomarkers, such as ctDNA clearance (HR for death 3.67) (36), absolute lymphocyte count (37), and PD-1⁺CD8⁺ T-cell density (39), offer real-time response monitoring. Novel approaches, including circulating cell-free DNA methylation models, achieve remarkable accuracy in predicting pCR (90.9%) and may enable future adaptive strategies (40).

Safety profiles are generally manageable. Grade 3–4 lymphopenia occurs in 66–92%, but immune-related AEs are mostly grade 1–2 (24,28). Serious complications, including fatal esophageal hemorrhage (14,16) and fistula (10–10.7% in heavily pretreated patients), demand vigilant monitoring and multidisciplinary management (21,22,24).

Future directions

The future must address the major knowledge gaps identified in Table 4. First, large-scale phase III randomized controlled trials with extended follow-up are urgently needed to confirm whether promising pCR improvements translate into sustained 5-year OS and disease-free survival benefits. Several ongoing trials, including RATIONALE-311 (NCT03957590), KEYNOTE-975 (NCT04210115), and NRG-GI006 (NCT04550260), will help establish the definitive role of immune checkpoint inhibitors combined with chemoradiotherapy in ESCC (22). Second, targeted strategies for prevention and management of severe AEs, particularly esophageal fistula and hemorrhage, need establishment through standardized protocols and risk stratification tools. Third, biomarker-driven adaptive strategies must be validated in prospective trials, moving beyond static PD-L1 expression to incorporate dynamic measures such as ctDNA kinetics, circulating cell-free DNA methylation patterns, and immune cell phenotyping. The remarkable accuracy of circulating cell-free DNA methylation-based models in predicting treatment response offers a particularly promising avenue for personalized therapy (40). Fourth, optimal integration of emerging technologies, including proton therapy, intensity-modulated proton therapy, and adaptive radiotherapy, may further enhance the therapeutic ratio by delivering higher radiation doses to tumors while sparing surrounding healthy tissues (10). Finally, as emphasized by the Zhejiang Province Expert Consensus (2025), multidisciplinary team management should be embedded throughout the patient journey, from initial diagnosis through post-treatment surveillance, to ensure optimal coordination of care and timely management of complications (40).

Conclusions

Neoadjuvant and definitive immunochemoradiotherapy represents a rapidly evolving paradigm for locally advanced ESCC. Current evidence demonstrates consistent pathological response improvements, with pCR rates of 37–60% in operable disease and up to 65% in converted unresectable patients. While concurrent regimens have established synergistic potential, emerging data increasingly support optimized sequential strategies that incorporate induction chemoimmunotherapy followed by chemoradiotherapy and maintenance immunotherapy. As demonstrated by Chen et al. (11), this approach yields substantial survival benefits with preserved quality of life, particularly for unresectable or advanced disease. However, these findings must be interpreted within the context of important limitations. The evidence base predominantly comprises phase II trials with modest sample sizes and limited follow-up; substantial heterogeneity in patient selection, treatment protocols, and endpoint definitions precludes cross-trial comparisons; safety data for rare severe events such as esophageal fistula remain incompletely characterized; and predictive biomarkers, including PD-L1 expression, have shown inconsistent utility. Despite these constraints, this review offers distinct strengths by providing a stage-specific, clinically oriented framework that delineates differential benefits and knowledge gaps across resectable, unresectable, and metastatic disease (Tables 3,4). Crucially, it emphasizes the emerging paradigm of treatment sequencing and integrates recently published data (2025–2026) to inform both clinical decision-making and future trial design. The path forward, as outlined in the Zhejiang Province Expert Consensus (2025), requires rigorous validation through large-scale phase III trials, continued refinement of predictive biomarkers (e.g., circulating cell-free DNA methylation), standardized multidisciplinary management, and proactive toxicity mitigation, particularly esophageal fistula risk in heavily pretreated populations. Through these concerted efforts, the remarkable promise of immunochemoradiotherapy can be translated into durable, real-world benefits across the locally advanced ESCC spectrum.

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-2026-1-0009/rc

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-2026-1-0009/prf

Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 82472663), the International Cooperation Projects of the Science and Technology Department of Sichuan Province (No. 2026YFHZ0053), and The “Flagship” Department Project of Integrated Traditional Chinese and Western Medicine.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-2026-1-0009/coif). The series “Multimodal Approach and Clinical Application for Esophageal Cancer” was commissioned by the editorial office without any funding or sponsorship. 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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