Highlights
– PALACE‑2 (multi‑center phase 1/2) evaluated preoperative pembrolizumab added to standard chemoradiotherapy (PPCT) in 143 patients with histologically confirmed, locally advanced, resectable esophageal squamous cell carcinoma (ESCC).
– Among 125 patients who underwent esophagectomy, pathologic complete response (pCR) was 43.2% (54/125); during neoadjuvant therapy 75.7% (106/140) experienced grade ≥3 adverse events (AEs).
– At median follow‑up 17.4 months, 1‑year disease‑free survival (DFS) was 91.1% and overall survival (OS) 96.5%.
– Single‑cell RNA sequencing (scRNA‑seq) and cytokine profiling implicated high interleukin‑6 (IL‑6) as a predictive biomarker of PPCT response; IL‑6 neutralization enhanced CD4+ T‑cell cytotoxicity in mouse models.
Background and disease burden
Esophageal cancer ranks among the most common and lethal malignancies worldwide, with squamous cell carcinoma (ESCC) predominating in many low‑ and middle‑income regions. ESCC is frequently diagnosed at a locally advanced stage because of its aggressive biology and late symptom onset. For patients with resectable, locally advanced disease, the current standard in many regions is neoadjuvant chemoradiotherapy followed by esophagectomy: the CROSS trial established a survival benefit and reported substantial pCR rates, particularly among squamous histology. Nonetheless, distant recurrence remains the predominant mode of failure after neoadjuvant chemoradiotherapy (nCRT) and surgery, motivating evaluation of systemic strategies to augment eradication of micrometastatic disease.
Immune checkpoint inhibitors (ICIs) targeting the PD‑1/PD‑L1 axis have shown activity in advanced ESCC (e.g., KEYNOTE‑590), and several neoadjuvant immunotherapy approaches are under investigation. Small pilot studies, including PALACE‑1, suggested that adding PD‑1 blockade to chemoradiotherapy before surgery is feasible and may increase pCR rates. PALACE‑2 was designed to provide larger‑scale prospective data on efficacy, safety, and immune correlates of preoperative pembrolizumab combined with chemoradiotherapy (PPCT) in resectable ESCC.
Study design
PALACE‑2 is a multicenter, single‑arm phase 1/2 trial (registered as NCT03792347 and NCT04435197) that enrolled patients with histologically confirmed, locally advanced, resectable ESCC. Key inclusion criteria included locally advanced stage disease judged operable, and adequate organ function. The neoadjuvant regimen combined pembrolizumab (anti‑PD‑1) with concurrent chemoradiotherapy using a taxane‑platinum doublet (paclitaxel or nab‑paclitaxel plus carboplatin) and radiotherapy; esophagectomy was performed 4–6 weeks after completion of neoadjuvant therapy.
The prespecified primary endpoint was pathological complete response (pCR) rate assessed on the surgical specimen. Secondary endpoints included safety (particularly grade ≥3 adverse events), surgical resection rate, perioperative outcomes, and short‑term survival (DFS and OS at 1 year). Translational endpoints included scRNA‑seq of tumor specimens, plasma cytokine profiling, and functional validation in in vivo tumor models to study changes in the tumor microenvironment (TME) associated with response.
Key findings and results
Enrollment and treatment delivery: 143 patients were enrolled; 140 received neoadjuvant PPCT and 125 proceeded to esophagectomy. Reasons for not undergoing surgery in the remaining patients included disease progression, treatment‑related complications, or patient choice (detailed breakdown not provided in the summary).
Pathologic response
Among the 125 patients who underwent resection, pCR (ypT0N0) occurred in 43.2% (54/125). This pCR rate is similar to historical pCR rates reported with nCRT alone in ESCC populations from CROSS (reported pCR ~49% in SCC subgroup) and the Chinese NEOCRTEC5010 trial (reported pCR 43.2%). The PALACE‑1 pilot study had previously reported an encouraging pCR of 55.6% with PPCT, but PALACE‑2 provides more robust, multi‑center prospective data.
Safety
During neoadjuvant therapy, grade 3 or higher adverse events occurred in 75.7% (106/140) of patients. The nature of high‑grade toxicities was not exhaustively detailed in the summary provided here; however, the high incidence underscores the need for careful perioperative management and patient selection when adding immunotherapy to chemoradiation. The authors report that overall safety was acceptable and perioperative mortality was not highlighted as excessive in the short‑term results.
Short‑term survival
With a median follow‑up of 17.4 months, the 1‑year DFS was 91.1% and OS 96.5% — encouraging early signals of disease control. These metrics are notable but require longer follow‑up and ideally comparative data to determine whether the addition of pembrolizumab reduces distant relapse beyond what nCRT alone achieves.
Tumor microenvironment and biomarker analyses
Using scRNA‑seq and cytokine profiling from tumor and blood samples, the investigators identified high IL‑6 levels as associated with response to PPCT. Mechanistic in vivo experiments showed that neutralizing IL‑6 enhanced the efficacy of immunotherapy, apparently by augmenting cytotoxic functions of CD4+ T cells. These translational findings point to IL‑6 as both a potential predictive biomarker and a therapeutic target to improve responses to combined modality therapy.
Expert commentary and interpretation
PALACE‑2 represents the first relatively large, multicenter phase 1/2 prospective study to evaluate pembrolizumab added to chemoradiotherapy prior to surgery in resectable, locally advanced ESCC. The trial demonstrates that the regimen is deliverable and yields a pCR rate (43.2%) comparable to published nCRT benchmarks in ESCC populations, with promising early survival outcomes.
Strengths of the study include its multicenter design, prospective collection of clinical and translational data, and incorporation of single‑cell and cytokine profiling with functional validation in preclinical models. The identification of IL‑6 as an immune‑modulatory mediator tied to treatment response is biologically plausible: IL‑6 promotes inflammation, can drive immunosuppressive myeloid programs, and has been implicated in resistance to ICIs in other cancers. The preclinical observation that IL‑6 blockade potentiates CD4+ T‑cell cytotoxicity provides a rationale for combinatorial strategies pairing IL‑6 inhibitors with PPCT in future trials.
Key limitations temper enthusiasm. PALACE‑2 is single‑arm without a randomized comparator; therefore, it cannot definitively demonstrate superiority of PPCT over standard nCRT. The high rate of grade ≥3 AEs during neoadjuvant treatment raises practical concerns about treatment tolerability and perioperative risk — detailed toxicity spectra, timing relative to surgery, and postoperative morbidity data are essential for clinical adoption. Follow‑up remains short; oncologic outcomes such as distant metastasis rates, disease‑specific survival, and long‑term toxicity will determine whether PPCT meaningfully changes the natural history of ESCC. Lastly, biomarker results are exploratory and require independent validation in randomized settings.
From a clinical perspective, PPCT may be considered investigational outside of clinical trials. For practices considering trials of neoadjuvant ICI plus chemoradiotherapy, PALACE‑2 provides useful safety benchmarks and highlights the importance of embedding translational studies to discover biomarkers and potential combination targets (for example, IL‑6 pathway inhibitors).
Conclusion and future directions
PALACE‑2 demonstrates that preoperative pembrolizumab added to chemoradiotherapy is feasible and yields a pCR rate in resectable, locally advanced ESCC similar to historical nCRT benchmarks, with encouraging early DFS and OS. The high incidence of grade ≥3 AEs during neoadjuvant therapy requires careful management. Importantly, the study provides mechanistic insight linking IL‑6 to treatment response and suggests that IL‑6 blockade may enhance anti‑tumor immunity when combined with PPCT.
Next steps should include randomized phase 3 trials comparing PPCT against modern nCRT, longer follow‑up to determine durability of DFS/OS benefits, and prospective validation of IL‑6 as a predictive biomarker. Rational combinatorial strategies that target IL‑6 or other immunosuppressive axes could be explored, ideally within biomarker‑enriched trial designs to maximize benefit while minimizing toxicity.
Clinical takeaways
– PPCT is deliverable and produces pCR in a substantial subset of patients with resectable ESCC (43.2% in PALACE‑2), but does not yet show clear superiority to nCRT alone in this single‑arm study.
– High rates of grade ≥3 toxicities during neoadjuvant therapy underscore the need for vigilant monitoring and perioperative coordination.
– IL‑6 emerged as a promising predictive biomarker and a potential therapeutic target to augment neoadjuvant immunotherapy efficacy.
Funding and clinicaltrials.gov
The PALACE‑2 trial is registered under NCT03792347 and NCT04435197. Funding sources were reported in the original publication (Li et al., Signal Transduction and Targeted Therapy, 2025); please refer to the manuscript for full disclosure of sponsor and grant details.
References
– Li C, Han Y, Zhao S, et al. Preoperative pembrolizumab (anti‑PD‑1 antibody) combined with chemoradiotherapy for esophageal squamous cell carcinoma: a phase 1/2 trial (PALACE‑2). Signal Transduct Target Ther. 2025 Nov 28;10(1):386. doi: 10.1038/s41392-025-02477-4.
– van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074–2084. (CROSS trial)
– Kato K, Sun JM, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy as first‑line therapy for advanced esophageal cancer: KEYNOTE‑590. N Engl J Med. 2021;384: [KEYNOTE‑590 primary report].
– Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–249.
Author note
This article synthesizes and interprets the PALACE‑2 trial findings and places them in the context of existing evidence on neoadjuvant strategies for ESCC. Clinicians should consult the primary publication for detailed methods, safety tables, and supplementary translational data before applying these findings to practice.
