Role of immunotherapy in esophageal cancer and its impact on surgical outcomes: a narrative review

Introduction

Background

Esophageal cancer is a globally prevalent malignancy and a leading cause of cancer-related death, particularly in East Asia and Africa, with nearly 511k cases and 445k deaths in 2022 and the highest rates in Eastern Asia and Southern/Eastern Africa (1,2). It consists primarily of two histologic subtypes: esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) (2).

Despite advances in multimodal therapy, esophageal cancer remains a disease with poor prognosis and high mortality, particularly in patients who present with locally advanced or unresectable disease (3). Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy remains the current standard of care for resectable esophageal cancer, with landmark trials like CROSS demonstrating durable survival benefits (4). For ESCC specifically, the phase III JCOG1109 (NeXT) randomized trial showed that neoadjuvant docetaxel-cisplatin-5-FU (DCF) improved overall survival (OS) versus cisplatin-5-FU, whereas preoperative CF-RT did not significantly improve survival over CF, informing current practice in Japan (5). However, recurrence rates remain substantial, and long-term survival is limited for many patients (6).

Current treatment options span four pillars. For resectable disease, esophagectomy is paired with nCRT (e.g., CROSS) or, particularly for adenocarcinoma, perioperative chemotherapy such as FLOT (7). Definitive radiotherapy/chemoradiotherapy provides a curative-intent alternative in unresectable/cervical tumors or for patients unfit for surgery. Immunotherapy has entered the perioperative pathway—most notably adjuvant nivolumab after nCRT and R0 resection—and is combined with chemotherapy in advanced disease per histology and programmed death-ligand 1 (PD-L1) status (8).

Rationale and knowledge gap

In recent years, immunotherapy—especially programmed death 1 (PD-1)/PD-L1 blockade—has demonstrated efficacy in improving survival across several solid tumors, including esophageal cancer (9). While several studies have investigated immunotherapy in metastatic and adjuvant settings, limited data are available regarding its effect on surgical outcomes and perioperative safety when used preoperatively (10,11). As immunotherapy becomes increasingly integrated into esophageal cancer treatment algorithms, it is critical to understand how these agents influence surgical feasibility, complication rates, and long-term oncologic outcomes.

Existing reviews summarize perioperative immunotherapy in esophageal cancer—e.g., Yoshii et al., 2024, Liu et al., 2023, Wei et al., 2024 and Shoji et al., 2024 (12-15). However, most prior reviews predate or briefly reference randomized perioperative chemo-IO (e.g., ESCORT-NEO), rarely standardize surgical endpoints (R0 resection, time-to-surgery, perioperative morbidity), give limited attention to conversion-to-surgery strategies, and seldom integrate translational ctDNA data. Our review (through May 28, 2025) updates the field by incorporating randomized chemo-IO evidence, systematically extracting surgical outcomes alongside pathological complete response (pCR)/major pathological response (MPR), adding conversion-to-resection data, and linking perioperative efficacy with biomarkers (including ctDNA) (12-14).

Objective

This review aims to provide an overview of the current landscape of immunotherapy in esophageal cancer, with a particular emphasis on its implications for surgical management. Specifically, we discuss the rationale, key clinical trial data, and emerging strategies surrounding the use of immune checkpoint inhibitors (ICIs) in both neoadjuvant and adjuvant settings, and their potential impact on resectability, perioperative outcomes, and long-term survival. We present this article in accordance with the Narrative Review reporting checklist (available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-21/rc).

Methods

To synthesize the current understanding of immunotherapy’s impact on surgical outcomes in esophageal cancer, a targeted literature review was conducted on literature available up to May 28, 2025. We searched PubMed and ClinicalTrials.gov, supplemented by backward citation tracking of pivotal guidelines and reviews. The search strategy combined both MeSH terms and free-text keywords, using combinations such as “Immunotherapy” OR “immune checkpoint inhibitors” OR “PD-1” OR “PD-L1” OR “nivolumab” OR “pembrolizumab”, AND “esophageal cancer” OR “esophageal neoplasms”, AND “surgery” OR “esophagectomy” OR “perioperative”. Filters applied included English language and human studies, with no restrictions on publication year. See Table S1 for detailed PubMed search strategy.

We included randomized controlled trials, cohort studies, systematic reviews, and clinical guidelines that addressed immunotherapy in ESCC or EAC, specifically when surgical endpoints or perioperative outcomes (e.g., resectability, pathological response, surgical morbidity) were reported. Preclinical studies, case reports, non-English publications, and studies lacking surgical relevance were excluded.

The study selection process was independently performed by two reviewers (Maya Abdelhamid and M.R.), with disagreements resolved through discussion and consensus. Although this was not a systematic review, methodological rigor was maintained by supplementing database searches with comprehensive clinical trial registry searches and incorporating expert recommendations.

Data extracted from eligible sources focused on clinical trial design, treatment regimens, tumor histology, pathological response rates (pCR, MPR), R0 resection rates, and perioperative safety metrics. These were synthesized narratively and supported by summary tables highlighting completed and ongoing trials of perioperative ICIs in esophageal cancer.

Additionally, we screened major congress abstracts (ASCO/ESMO/AACR). When data were available only in abstract form, this is indicated in text.

Furthermore, we qualitatively appraised study quality across simple domains (study design, sample size, endpoint maturity, reporting of surgical outcomes, and potential sources of bias); no formal meta-analysis or GRADE rating was performed. Table 1 summarizes the full search process.

Immunologic rationale for perioperative integration of ICIs

Immune checkpoint inhibition reverses the functional exhaustion of cytotoxic T cells, restoring their ability to recognize and attack tumor cells effectively (16). In esophageal cancer, the tumor microenvironment is often rich in immune-suppressive signals that blunt natural immune responses. By blocking these checkpoints—particularly the PD-1/PD-L1 axis—ICIs reinvigorate immune surveillance and promote tumor regression (17).

Neoadjuvant use of immunotherapy may help shrink tumors prior to surgery, making resection easier and more effective, while priming the immune system against residual disease (18). On the other hand, adjuvant administration post-surgery aims to eliminate microscopic disease that might otherwise lead to recurrence (19). Both neoadjuvant and adjuvant strategies aim to eliminate macroscopic and microscopic disease, while also inducing long-term immunologic memory to prevent recurrence (20). The integration of immunotherapy into the surgical timeline represents a promising step toward durable remission and improved overall outcomes in esophageal cancer.

Neoadjuvant immunotherapy and surgical outcomes

Recent clinical trials have demonstrated that incorporating ICIs into nCRT regimens can significantly enhance tumor response in resectable ESCC (21-23).

pCR—defined as the absence of viable tumor cells in resected specimens—has been reported in up to 55.6% of patients in clinical trials in the neoadjuvant setting such as PALACE-1, suggesting a synergistic effect between immunotherapy and chemoradiation (21). Trials such as PEN-ICE and PALACE-1 have also shown high MPR rates (69.2% and 89%, respectively), supporting robust tumor regression (21,23). These findings are summarized in Table 2, which highlights pCR and MPR outcomes across key recent neoadjuvant immunotherapy trials in resectable ESCC.

Beyond early single-arm signals, randomized data now support neoadjuvant chemo-immunotherapy in resectable ESCC. In ESCORT-NEO, camrelizumab combined with platinum-based chemotherapy increased pathological response compared with chemotherapy alone while maintaining perioperative feasibility—R0 resection rates remained high and postoperative complication rates were comparable between arms (27).

Consistent neoadjuvant signals also come from prospective single-arm studies. KEEP-G 03 (sintilimab + platinum chemotherapy) reported notable pCR/MPR rates with high R0 resection and manageable toxicity, supporting surgical feasibility. In the multicohort Phase I FRONTiER program, adding nivolumab to standard CF/DCF regimens showed acceptable safety and encouraging pathological regression. Taken together with PALACE-1 and PEN-ICE, these data reinforce that perioperative PD-1 blockade can be integrated without compromising resectability (15,28).

Notably, Keystone-001 (pembrolizumab + paclitaxel/cisplatin) paired robust pathological responses with deep translational profiling—including immune-microenvironment features and circulating tumor DNA (ctDNA) dynamics—offering a mechanistic rationale for biomarker-guided perioperative strategies (29).

Importantly, these immune-based regimens appear to maintain surgical safety and feasibility. Data from multiple trials indicate that key intraoperative parameters—such as operative time, intraoperative blood loss, and postoperative complication rates—remain largely unchanged compared to standard therapy (11,30).

Notably, surgery was generally timely; while isolated delays occurred (e.g., seven cases in NICE), R0 rates remained high and overall feasibility was preserved. While grade ≥3 adverse events such as lymphopenia and pneumonia were observed (e.g., in PALACE-1 and NICE), these were largely manageable and did not compromise surgical candidacy (21,22).

Together, these findings support the feasibility of combining ICIs with surgery and suggest a potential shift toward more personalized, immune-based perioperative strategies in ESCC management. Ongoing randomized studies will be critical to confirm these promising early-phase results. A summary of the most related immunotherapy trials in esophageal cancer is outlined in Table 3.

In parallel, adding PD-1 blockade to standard nCRT appears feasible. In NEOCRTEC1901 (toripalimab + nCRT), investigators reported meaningful pCR/MPR with timely surgery and acceptable perioperative safety. While randomized confirmation is pending, these results suggest synergy among radiotherapy, chemotherapy, and PD-1 inhibition in potentially resectable ESCC (38).

For initially borderline/unresectable ESCC, ICI-containing sequences may expand operability. NEXUS-1 employed nCRT followed by immunochemotherapy and achieved high conversion-to-resection rates with acceptable safety, highlighting a potential pathway to increase resectability in locally advanced disease (40).

Adjuvant immunotherapy: CheckMate 577 and beyond

Adjuvant immunotherapy has emerged as a transformative approach for patients with residual disease following trimodality therapy for esophageal or gastroesophageal junction cancer. Clinical evidence, primarily from the CheckMate 577 trial, has shown that adjuvant nivolumab significantly improves disease-free survival (DFS) in patients with residual disease following nCRT and R0 resection. This benefit was observed across both squamous cell carcinoma and adenocarcinoma histologies, with a median DFS of 22.4 months in the nivolumab group versus 11.0 months in the placebo group (hazard ratio 0.69, P<0.001), supporting broad applicability regardless of histological subtype (19).

Moreover, immune-related adverse events associated with adjuvant therapy have generally been manageable and do not appear to compromise postoperative recovery or delay healing. Patients tolerated the therapy well, with most side effects being low-grade and responsive to standard management. Importantly, no increase in postoperative morbidity was reported during adjuvant therapy initiation, indicating feasibility of sequential administration (19).

The success of CheckMate 577 has catalyzed further investigations into optimizing adjuvant immunotherapy. Strategies under exploration include biomarker-guided patient selection (e.g., PD-L1 expression, ctDNA) and combination immunotherapy regimens that may further reduce recurrence risk. As the field evolves, adjuvant immune checkpoint blockade is poised to become a foundational component of personalized perioperative management in esophageal cancer (41).

Perioperative safety and immune-related toxicities

Immune-related toxicities—such as pneumonitis, dermatitis, and endocrinopathies—are typically low-grade and rarely life-threatening, as seen in Table 4. These toxicities are typically reversible with standard interventions such as corticosteroids or hormone replacement, and they seldom necessitate treatment discontinuation or delay surgical intervention (42,43).

Across multiple prospective neoadjuvant studies in resectable ESCC—including PALACE-1, NICE, and PEN-ICE—ICIs have been shown to be safely integrated without increasing perioperative risk. For example, PALACE-1 reported 65% Grade ≥3 AEs (mainly lymphopenia), but no delays in surgery occurred. Similarly, the NICE trial noted that despite grade 3–5 AEs in 53.3% of patients, R0 resection was achieved in 100%, and only 7 patients experienced surgical delay. PEN-ICE also demonstrated a high MPR rate (69.2%) with no unexpected immune-mediated complications or impact on surgical feasibility (21-23).

These observations are consistent with randomized ESCORT-NEO, where postoperative complication rates were similar between chemo-immunotherapy and chemotherapy alone. Moreover, although EC-CRT-001 evaluated toripalimab with definitive CRT (non-surgical intent), its safety profile further supports the tolerability of combining PD-1 blockade with thoracic chemoradiation (27,39).

Key surgical metrics—such as 30-day mortality, infection rates, anastomotic leak, and respiratory function—remained consistent with outcomes observed in standard chemoradiotherapy protocols (10,45). Concerns specific to esophagectomy, such as pulmonary reserve and wound healing, were not adversely affected. In some cases, the addition of ICI may even facilitate resection by reducing tumor volume or metabolic activity (44).

Across early-phase clinical trials evaluating the addition of ICIs to nCRT in ESCC, perioperative mortality rates have remained low. For example, the NICE trial reported no in-hospital or postoperative 30-day mortality among 47 resected patients (22). Similarly, in PALACE-1, there were no reported intraoperative or postoperative deaths among the resected cohort (21). These findings suggest that integrating ICIs into the perioperative setting does not significantly increase surgical mortality, reinforcing their feasibility and safety in curative-intent treatment protocols.

These findings suggest that perioperative immune checkpoint blockade, when administered with appropriate patient selection and toxicity management protocols, can be both biologically effective and surgically safe, supporting its continued integration into multimodal esophageal cancer treatment strategies.

Biomarkers and patient selection

An essential component of immunotherapy success lies in the identification of patients most likely to benefit from treatment. Among established biomarkers, PD-L1 expression, commonly quantified by the combined positive score (CPS), has demonstrated predictive value for ICI response, particularly in ESCC (9,35,42). For instance, a CPS ≥10 was associated with improved OS in patients receiving pembrolizumab as first-line therapy in trials like KEYNOTE-590 (35). However, the predictive utility of PD-L1 is not absolute, with inconsistent thresholds and varying predictive power observed across different studies and histological subtypes (46). Beyond PD-L1, microsatellite instability-high (MSI-H) status and high tumor mutational burden (TMB-H) are well-established biomarkers for ICI sensitivity across various solid tumors, including a subset of esophageal cancers (47,48). These genomic alterations are associated with increased neoantigen load and higher tumor immunogenicity, rendering tumors more susceptible to immune checkpoint blockade (49).

Prospective perioperative datasets are beginning to link biology with outcome. In Keystone-001, paired tissue and blood profiling (including ctDNA dynamics) correlated immune activation with pathological response, suggesting that perioperative monitoring could refine patient selection and inform adjuvant ICI duration (29).

Furthermore, liquid biopsy techniques, particularly the analysis of ctDNA, are rapidly emerging as valuable tools. ctDNA shows promise not only in non-invasive monitoring for minimal residual disease (MRD) following surgery but also in stratifying recurrence risk and potentially guiding the need for and duration of adjuvant immunotherapy (50).

Current trials and future directions

Seminal trials have significantly influenced the landscape, with studies like KEYNOTE-975 (pembrolizumab + CRT), which has now completed recruitment, and the published phase III ESOPEC trial (comparing FLOT chemotherapy vs. CROSS chemoradiotherapy), providing crucial data for optimizing perioperative regimens; ESOPEC showed a significant OS benefit favoring FLOT (e.g., median OS ~ 66 vs. 37 months; HR for death ≈0.77), with consistent advantages across key secondary endpoints (7,51,52).

Ongoing randomized trials such as SCIENCE (sintilimab with neoadjuvant chemotherapy or chemoradiotherapy versus standard approaches) will clarify the contribution of PD-1 blockade to pCR, DFS, and resection quality in resectable ESCC (37).

In addition to pembrolizumab-based trials such as KEYNOTE-975, several studies are currently evaluating Tislelizumab in both advanced and perioperative esophageal cancer. In advanced ESCC, RATIONALE-302 (second line) and RATIONALE-306 (first line) established OS benefit. RATIONALE-311 evaluates CRT with or without tislelizumab in localized, inoperable ESCC (non-surgical intent), informing CRT + PD-1 tolerability. RATIONALE-315 (perioperative NSCLC) showed EFS/MPR benefit and serves as adjacent perioperative evidence rather than esophageal-specific data (53-56). Although not restricted to esophageal cancer, the Published phase III MATTERHORN trial (durvalumab plus perioperative FLOT chemotherapy) improved event-free survival in gastric/GEJ adenocarcinoma (includes GEJ), providing adjacent support relevant to perioperative strategies in EAC/GEJ (57).

While ESOPEC did not directly involve immunotherapy in its comparative arms, the integration of ICIs into neoadjuvant and adjuvant settings is actively being explored in other ongoing studies. Collectively, these trials aim to refine patient selection, maximize tumor regression, and assess whether neoadjuvant or adjuvant immunotherapy confers greater survival benefit (7,51). Key ongoing and recently completed trials in this evolving landscape are summarized in Table 5.

In adenocarcinoma-predominant gastric/GEJ disease, DANTE/FLOT-8 (atezolizumab + FLOT) and the Phase III MATTERHORN (durvalumab + FLOT; event-free survival benefit) provide supportive perioperative signals that, while in adjacent populations, reinforce the perioperative ICI concept for upper GI adenocarcinoma and inform strategies for esophageal/GEJ cohorts (36,57).

Looking further ahead, next-generation immunotherapies are under active clinical investigation. Strategies such as personalized neoantigen vaccines, bispecific antibodies, and adoptive T-cell therapies offer exciting possibilities for enhancing immune responses with greater specificity. These innovations may eventually be incorporated into multimodal surgical workflows, tailoring treatment to a tumor’s unique immunologic profile and redefining the curative approach to esophageal cancer (14,58-60).

Quality of evidence and risk of bias

The current evidence base is heterogeneous. Apart from adjuvant CheckMate 577 and the randomized neoadjuvant ESCORT-NEO, most perioperative studies in ESCC are single-arm, early-phase trials with modest sample sizes, limiting precision and increasing susceptibility to selection bias (8,11,14,27,41). Many reports rely on surrogate endpoints (pCR/MPR) with immature OS/DFS and inconsistent reporting of surgical metrics (e.g., time-to-surgery, R0 definition, standardized 30-day morbidity/mortality), which complicates cross-trial comparisons (11,41). Histology and geography also constrain generalizability: ESCC cohorts (often East Asian) predominate, whereas EAC/GEJ populations are under-represented and sometimes show different signals (e.g., EA2174 negative pCR result in adenocarcinoma) (14). Biomarker analyses (e.g., PD-L1 CPS, ctDNA) are frequently exploratory with variable assays/thresholds and limited stratified outcomes. Finally, several data points derive from interim or abstract-only reports, with potential publication/reporting bias (36,37).

Evidence snapshot for clinicians:

Higher strength: CheckMate 577 (adjuvant nivolumab, randomized), ESCORT-NEO (neoadjuvant chemo-IO, randomized) (8,27).

Moderate strength: multicenter phase II neoadjuvant studies reporting surgery (e.g., PALACE-1, NICE, PEN-ICE) (21,22,24).

Lower strength: small single-center phase I/II, conversion-to-surgery cohorts, abstract-only/interim analyses (15,28,29,36,37,40).

Taken together, perioperative ICI appears feasible and can increase pathological response without clear perioperative harm in ESCC, but practice-changing conclusions for survival—especially in adenocarcinoma—await confirmation in larger randomized trials with mature OS/DFS and standardized surgical endpoints.

Strengths and limitations of this review

This narrative review provides a contemporary synthesis (to May 28, 2025), integrating randomized perioperative evidence (e.g., ESCORT-NEO) alongside recent trials and context from adjacent upper-GI studies. We standardized surgical endpoints (pCR/MPR, R0 resection, timing to surgery, perioperative morbidity) and, where available, included OS/DFS. The review also incorporates conversion-to-surgery data and biomarker insights (e.g., PD-L1/CPS, ctDNA) and distinguishes histology-specific patterns (ESCC vs. EAC), highlighting negative signals where relevant (e.g., EA2174).

As a narrative (not systematic) review, we did not register a protocol, perform a quantitative meta-analysis, or apply a formal risk-of-bias/GRADE framework. The evidence base is heterogeneous (study designs, regimens, endpoints) and often relies on single-arm, early-phase cohorts with modest sample sizes; several reports are interim or abstract-only, increasing the chance of publication/reporting bias. English-language restrictions may omit relevant studies. Generalizability is limited by the predominance of ESCC and East Asian cohorts and by immature OS/DFS in many perioperative datasets—particularly for adenocarcinoma. Real-world surgical outcomes may also vary by center and technique.

Implication

Findings should be interpreted with these constraints in mind; additional large, randomized trials with standardized surgical outcome reporting and mature survival data—especially in EAC/GEJ—are needed to inform practice.

Conclusions

Immunotherapy has moved beyond metastatic care into the perioperative setting for esophageal cancer. Neoadjuvant PD-1/PD-L1 blockade combined with chemoradiation, or chemotherapy consistently increases pathological response in ESCC without compromising surgical feasibility or short-term safety, and adjuvant nivolumab after nCRT and R0 resection prolongs DFS across histologies.

While these data support integrating ICIs into multimodal care, the evidence base remains heterogeneous, with limited mature OS/DFS in many perioperative cohorts and uncertainty greatest in adenocarcinoma. Biomarkers—including PD-L1 CPS, MSI-H/TMB-H, and ctDNA—offer a path to better patient selection and treatment tailoring. Active randomized trials should clarify sequencing, duration, and combination strategies, guiding broader, evidence-based adoption in multidisciplinary practice.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-21/rc

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-21/prf

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-25-21/coif). M.R. serves as an unpaid editorial board member of Annals of Esophagus from April 2025 to March 2027. 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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