Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC), although perioperative immunotherapy has shown considerable promise. The integration of immunotherapy with nCRT (nICRT) is an innovative treatment paradigm and early-phase studies have reported enhanced pathological complete response (pCR) rates. However, comprehensive evaluations of safety, long-term prognosis, and recurrence patterns are lacking. In this multicenter real-world study, the clinical efficacy, recurrence patterns, and potential prognostic biomarkers were evaluated in patients with LA-ESCC receiving nICRT followed by esophagectomy. Clinical data from patients with LA-ESCC who underwent nICRT followed by esophagectomy between September 2020 and February 2023 were retrospectively analyzed across three tertiary cancer centers. Baseline inflammatory markers (platelet-to-lymphocyte ratio [PLR] and neutrophil-to-lymphocyte ratio [NLR]) were calculated from pretreatment complete blood counts. Treatment-related adverse events (AEs), survival outcomes, and recurrence patterns were rigorously assessed. Among the 71 enrolled patients, all achieved R0 resection (100%). The pCR and major pathological response (mPR) rates were 50.7% (36/71) and 77.5% (55/71), respectively. Grade ≥ 3 AEs occurred in 25 patients (35.2%), predominantly neutropenia (31.0%, 22/71) and radiation oesophagitis (7.0%, 5/71). Postoperative complications included anastomotic leakage (4.2%, 3/71) and pneumonia (15.5%, 11/71). With a median follow-up of 36.5 months (95% CI: 29.8-43.2), the 2- and 3-year overall survival (OS) rates were 81.5 and 70.6%, and the disease-free survival (DFS) rates were 70.3 and 58.0%, respectively. Recurrences included locoregional (12/71, 16.9%; 11 nodal, 1 anastomotic) and distant metastases (23/71, 32.4%; lung [8], bone [5], pleura [5], liver/brain/adrenal gland/chest wall [2 each] and extra-nodal [5]). Multivariate analysis revealed that pathological N stage was an independent prognostic factor for both OS and DFS (P < 0.05), whereas elevated PLR was associated with worse DFS (P < 0.05). Notably, non-pCR patients receiving adjuvant therapy (n = 20) had superior 2-year OS (75% versus 53.3%) and DFS (54.5% versus 33.3%) than untreated patients did (n = 15; P < 0.05). nICRT demonstrates acceptable safety and efficacy in patients with LA-ESCC, with distant metastasis as the main recurrence pattern. The pretreatment PLR may serve as a prognostic biomarker, and adjuvant therapy improves survival in non-pCR patients. These findings warrant validation in prospective studies. The trial registration number is NCT06828718.

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis owing to chemoresistance to neoadjuvant chemotherapy (NAC). Ferroptosis, regulated by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1), is a potential therapeutic target. This study investigated the significance of GPX4 and FSP1 in NAC-treated ESCC. We analyzed 97 patients with ESCC who underwent NAC and esophagectomy. GPX4 and FSP1 expressions were assessed in relation to clinicopathological factors and survival. Three ESCC cell lines were exposed to cisplatin or 5-fluorouracil with or without the ferroptosis inhibitor liproxstatin-1, GPX4 inhibitor RSL3, or FSP1 inhibitor iFSP1. Cell viability, mRNA expression, and drug interactions were evaluated. Post-NAC GPX4-positivity (44.3%) was associated with aggressive clinicopathological features, poor histopathological effect, and worse overall and relapse-free survival. Post-NAC FSP1-positivity (28.9%) was associated with poor histopathological effects. Persistent GPX4-positivity from pre- to post-NAC was an independent prognostic factor for poor relapse-free survival (hazard ratio=2.098; 95% confidence interval=1.013-4.345). Cisplatin up-regulated GPX4 mRNA expression, particularly in KYSE70 cells. Liproxstatin-1 partially attenuated chemotherapy-induced cytotoxicity without altering the half-maximal inhibitory concentration. RSL3 enhanced cisplatin and 5-fluorouracil effects in a cell line-dependent manner. GPX4 mediates tumor aggressiveness and chemoresistance in NAC-treated ESCC. Persistent GPX4-positivity may serve as a prognostic biomarker, and targeting the GPX4-mediated ferroptosis pathway with standard chemotherapy may overcome resistance in advanced ESCC.

Randomized Study on Different Radiation Doses in Neoadjuvant Chemoradiotherapy for Resectable Thoracic Esophageal Squamous Cell Carcinoma (Neo-DRATEC Trial).

Radiotherapy with versus without concurrent immunotherapy following neoadjuvant chemoimmunotherapy in unresectable locally advanced esophageal squamous cell carcinoma.

Neoadjuvant chemoimmunotherapy (nCIT) has improved outcomes in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). However, accessible and reliable biomarkers to predict survival and pathological response remain limited. This study assessed the prognostic and predictive value of the Global Immune-Nutrition Index (GINI), cytokeratin-19 fragment (CYFRA 21 - 1), fibrinogen-albumin ratio index (FARI), and a composite score combining these markers-the GINI-CYFRA 21 - 1-FARI (GCF) score. A retrospective analysis was conducted on 138 LA-ESCC patients who received nCIT followed by radical esophagectomy between 2021 and 2023. Optimal cut-off values for GINI, CYFRA 21 - 1, and FARI were determined using X-tile software. The composite GCF score was developed accordingly. Associations with disease-free survival (DFS) were evaluated using Kaplan-Meier analysis and multivariable Cox regression. Predictive performance was assessed via time-dependent ROC curves. Tumor regression grade (TRG) was analyzed using logistic regression, and a nomogram was constructed to predict pathological response. Elevated levels of GINI (median DFS: 20 vs. not estimable [NE] months; p = 0.001), CYFRA 21 - 1 (19 vs. NE months; p < 0.001), FARI (11 vs. 26 months; p < 0.001), and higher GCF scores (0 vs. 1 vs. ≥2: 18 vs. 22 vs. NE months; p < 0.001) were associated with worse DFS. The GCF score was independently predictive of DFS (low vs. high: HR = 0.264; p = 0.028) and demonstrated consistent discriminative capacity. For pathological response, the GCF score showed predictive value for TRG (AUC = 0.625; p = 0.004) and was independently associated with poor TRG (high vs. low: OR = 2.170; p = 0.048). A nomogram incorporating the GCF score outperformed models excluding it (AUC: 0.787 vs. 0.662; p < 0.05). The GCF score-a composite of GINI, CYFRA 21 - 1, and FARI-independently predicts DFS and pathological response following nCIT and surgery in LA-ESCC, and may hold potential as a practical, blood-based biomarker. Its integration significantly enhances predictive model performance and may aid in individualized patient risk stratification.

ABSTRACTBackgroundDose exposure to supraventricular cardiac conduction system doses has been reported to be associated with distinct arrhythmia classes after thoracic radiotherapy, but its impact in esophageal squamous cell carcinoma (ESCC) remains unknown.Materials and MethodsLocally advanced ESCC treated with neoadjuvant chemoradiotherapy (nCRT) were included. The primary endpoint was grade ≥ 3 adverse cardiac arrhythmia events. Prediction performance was evaluated through time‐dependent receiver operating characteristic curves, and competing risk frameworks were implemented to quantify the cumulative incidence of distinct cardiac arrhythmia.ResultsOf 358 patients, 84.9% were men, with a median age of 66 years (range: 39–79 years). A total of 60 (16.8%) patients experienced at least 1 grade ≥ 3 arrhythmia, with a median time to first arrhythmia of 13 months (95% CI: 12–15 months). The 2‐year cumulative incidences of distinct cardiac arrhythmia were 8.89% for AF, 2.96% for atrial flutter, and 5.12% for other SVT. Baseline coronary heart disease was a risk factor for all types of arrhythmia (p < 0.05). After adjusting for baseline cardiovascular risk factors, Heart Dmax (sHR 3.69, p = 0.0024) was associated with AF, Heart volume receiving 5 Gy with atrial flutter (sHR: 9.35, p = 0.0077), and Heart volume receiving 40 Gy (sHR 5.72, p = 0.00078) with other SVT.ConclusionGrade ≥ 3 cardiac arrhythmia associated with thoracic radiation occurs in 16.7% of ESCC patients undergoing nCRT within a median time of 13 months. The radiation dose exposure of the supraventricular cardiac conduction system is not associated with increased cardiac arrhythmia. Specific arrhythmia subtypes exhibited differential associations with distinct dose‐volume parameters of whole heart irradiation.

ObjectivesNeoadjuvant therapy (NAT) significantly improves the pathologic complete response (pCR) rates in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Emerging evidence suggests that patients with pCR may experience favourable outcomes and could be considered for active surveillance strategies to delay surgery. This study aims to develop a clinical-radiomics model to predict pCR after NAT in ESCC.MethodsWe retrospectively enrolled 236 patients with locally advanced ESCC who received NAT at our centre and randomly assigned them to training and test cohorts (3:2 ratio). Radiomics features were extracted from tumour regions segmented on post-NAT contrast-enhanced computed tomography (CT) scans. After feature selection, a predictive model integrating radiomics and clinical variables was developed using logistic regression and visualized as a nomogram. Model performance was evaluated using area under the curve (AUC), accuracy, sensitivity, and specificity.ResultsThe clinical-radiomics model achieved an AUC of 0.91 (95% confidence interval [CI]: 0.86-0.95), accuracy of 0.84, sensitivity of 0.89, and specificity of 0.81 in the training cohort, and an AUC of 0.84 (95% CI: 0.76-0.92), accuracy of 0.78, sensitivity of 0.84, and specificity of 0.74 in the test cohort. Calibration curves demonstrated good agreement between predicted and observed outcomes, and decision curve analysis confirmed the model’s clinical utility.ConclusionsThe clinical-radiomics model accurately predicts pCR following NAT in ESCC and may guide personalized treatment strategies.

Efficacy of neoadjuvant chemoradiotherapy with 5-fluorouracil/cisplatin versus paclitaxel/cisplatin in esophageal squamous cell carcinoma: A single-institute real-world study.

Clinical observation of anti-PD-1/PD-L1 immunotherapy plus concurrent chemoradiotherapy for locally advanced esophageal squamous cell carcinoma.

Iparomlimab and tuvonralimab (QL1706) combined definitive chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma (QL1706-IIT-02): a single arm, phase 2 trial.

Molecular mechanism underlying radiation resistance in esophageal squamous cell carcinoma.

Immune checkpoint inhibitors (ICIs) significantly improve the survival of patients with advanced esophageal squamous cell carcinoma (ESCC). However, reliable biomarkers for predicting treatment response and prognosis have not yet been identified. This study investigated the relationship between specific lymphocytes in peripheral blood prior to treatment and the efficacy of ICIs, as well as prognosis, in patients with advanced ESCC. Peripheral blood samples were prospectively collected from 97 patients with stage III-IVB ESCC before ICI treatment. Flow cytometry was used to detect and quantify peripheral blood lymphocyte subsets, including natural killer (NK) cells, B cells, T cells, CD4+ T cells, and CD8+ T cells, along with the CD4+/CD8+ T cells ratio. Treatment response was classified according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). The patients with a complete response (CR) or partial response (PR) were allocated to the response group, while those with stable disease (SD) or progressive disease (PD) were allocated to the non-response group. The Chi-squared test and U test were used to assess the qualitative and quantitative differences between groups, and receiver operating characteristic (ROC) curves were used to evaluate the predictive efficacy of lymphocyte subpopulations for ICI response. Kaplan-Meier and log-rank tests were used to compare disease-free survival among the groups. Of the 97 patients, 42.3% (41/97) responded to ICI treatment. The baseline characteristics, including age, gender, and ICI drugs, were balanced between the response and non-response groups. The patients in the response group exhibited significantly higher baseline CD4+ T-cell counts (42.60 vs. 34.45, P=0.001) and CD4+/CD8+ ratios (2.02 vs. 1.54, P=0.01). The area under the curve (AUC) for the CD4+ T-cell count and the CD4+/CD8+ ratio were 0.701 and 0.648, respectively. Stratified analyses revealed variations in predictive efficacy based on staging and ICI drugs. In the stage III patients, higher AUC values were observed (0.883 for the CD4+ T-cell count and 0.833 for the CD4+/CD8+ ratio). Conversely, in the stage IV patients, a correlation was only observed between low B-cell counts and an improved response (6.40 vs. 8.65, P=0.02), with an AUC of only 0.510. Higher CD4+ T-cell counts were associated with improved responses in the patients receiving anti-programmed death-ligand 1 (PD-L1) therapy (40.00 vs. 30.30, P=0.03), with an AUC of 0.806. The results of the patients who received anti-programmed cell death protein 1 (PD-1) therapy were consistent with those of the overall population, but the corresponding AUC values were lower (0.693 and 0.638, respectively). The prognostic analysis revealed that lower NK cell counts before treatment were correlated with longer disease-free survival. In patients with advanced ESCC, specific lymphocyte subsets in peripheral blood before treatment are closely associated with ICI efficacy and patient prognosis, and thus could potentially guide treatment decisions.

Aortoesophageal fistula (AEF) is a rare but invariably life-threatening conditio. The optimal treatment for AEF resulting from postoperative anastomotic leakage following esophageal cancer surgery remains a significant clinical challenge. Here, we report a detailed case of AEF caused by anastomotic leakage from a thoracic esophageal anastomosis after esophageal cancer resection, which was successfully managed with emergent thoracic endovascular aortic repair (TEVAR) for hemorrhage control, followed by elective surgical intervention comprising esophagogastric re-anastomosis and aortic fistula repair with a bovine pericardial patch. The patient achieved long-term survival. A 68-year-old male underwent minimally invasive McKeown esophagectomy with intrathoracic esophagogastric anastomosis after neoadjuvant chemotherapy and immunotherapy for advanced esophageal squamous cell carcinoma (SCC). Postoperatively, the patient experienced fever followed by hematochezia and hematemesis. Emergency endoscopy was unsuccessful in controlling the active arterial bleeding at the inflamed anastomotic site. Enhanced CT angiography (CTA) did not reveal a definitive aortoesophageal fistula, and subsequent transarterial embolization of the right gastric artery (confirmed by procedural records) failed to control the condition. The patient developed hemorrhagic shock manifested by loss of consciousness and hypotension. A repeat enhanced CT scan revealed active contrast extravasation from the descending aorta into the gastric conduit. An emergency TEVAR was performed to stabilize the hemodynamics. On postoperative day 10, we performed surgical exploration, which confirmed resection of the esophagogastric anastomotic leak, direct repair of the aortic wall defect, and reconstruction via esophagogastric anastomosis with the remnant stomach. Intraoperatively, a stapler clip from previous endoscopic hemostasis was identified as the potential culprit for the fistula formation. Ten months after the onset of AEF, the patient continued chemotherapy and led a normal daily life. This case underscores that TEVAR is an effective and life-saving hemostatic method for managing life-threatening hemorrhage from AEF. However, TEVAR alone cannot ensure long-term survival due to its inability to control the underlying infection and address the gastrointestinal defect. Long-term survival requires subsequent definitive surgical repair of both the esophageal and aortic components.

Construction and validation of a prediction model for postoperative complications of elderly patients with locally advanced esophageal squamous cell carcinoma based on POSSUM system and inflammatory factors.

The mechanisms underlying resistance to neoadjuvant immunotherapy and chemoradiotherapy (nICRT) in locally advanced esophageal squamous cell carcinoma (ESCC) remain poorly understood. Through a single-arm phase II trial (n = 22) with 44.4-month median follow-up, we observed a significant survival disparity: patients achieving major pathologic response (MPR) exhibited superior 3-year event-free survival (EFS) and overall survival (OS), with no recurrence in MPR patients versus 71.4% recurrence in non-major pathological response (NMPR) patients (HR = 17.69, 95% CI 2.25-139.20, p = 0.0063). Integrating single-cell RNA/TCR sequencing and functional validation, we identified a PRDM1+ malignant cell subcluster enriched in NMPR patients and associated with treatment resistance. These cells exhibit strong lipid peroxidation characteristics, a state linked to the transcriptional activation of CTSB and MFSD12 mediated by PRDM1. This state renders the PRDM1+ malignant cell cluster more susceptible to ferroptosis induction. PRDM1+ cells further recruited immunosuppressive regulatory T cells (Tregs) through IL1A-IL1R2 interactions and activated lipid-metabolizing TREM2+ macrophages via CD47-SIRPA signaling, fostering an immune-evasive microenvironment. Conversely, MPR patients displayed expanded cytotoxic T-effector clones with enhanced tumor-killing capacity. Our findings identify PRDM1 as a key factor associated with nICRT resistance and suggest that targeting ferroptosis pathways or disrupting PRDM1+ cell-mediated immune suppression may represent a viable strategy in ESCC. Clinical trial registration number: NCT03940001.

The survival benefits of neoadjuvant chemotherapy combined with immunotherapy in locally advanced esophageal squamous cell carcinoma (ESCC) remain unclear, with treatment responses varying due to tumor microenvironment (TME) heterogeneity. In this phase II study, 24 patients received neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin, with major pathological response (MPR), disease-free survival (DFS), and overall survival (OS) as primary endpoints. Results showed a 41.7% MPR rate, with 3 year DFS and OS rates of 75.0% and 79.2%, respectively. The PD-L1 expression of all patients increased during treatment; and its post-treatment levels were more strongly associated with the response to PD-1 inhibitors than pre-treatment levels. Besides, the mass spectrometry-based proteomic quantification identified 9 downregulated proteins in responders, including immune regulation-related proteins and peptidyl-serine phosphorylation proteins, revealing the TME changes linked to therapy efficacy. Additionally, 14 differentially expressed proteins were found at baseline between responders and non-responders, with high CD44 expression correlating with a favorable anti-PD-1 response. Post-treatment analysis revealed 27 differential proteins, 10 of which negatively correlated with efficacy. In conclusion, neoadjuvant sintilimab plus chemotherapy demonstrates promising efficacy and safety. Proteomic profiling of the TME further elucidates the heterogeneity of immunotherapy responses, offering insights for precision strategies in ESCC neoadjuvant therapy. Trial registration This study was prospectively registered in the Chinese Clinical Trial Registry (ChiCTR2000041081).

BackgroundThe combination of immune checkpoint inhibitors with chemotherapy is a standard first-line treatment for advanced esophageal squamous cell carcinoma. However, robust data regarding the efficacy and safety of this approach specifically in patients aged 75 years and older are scarce, as this population is frequently underrepresented in pivotal clinical trials.ObjectiveThis study aimed to evaluate the real-world treatment outcomes and safety profile of first-line immunotherapy in patients aged ≥75 years with advanced esophageal squamous cell carcinoma.MethodsWe conducted a retrospective, single-center cohort study. Sixty-one patients aged ≥75 years with histologically confirmed, advanced esophageal squamous cell carcinoma (stage III/IV) who initiated first-line immune checkpoint inhibitors (as monotherapy or combined with chemotherapy/antiangiogenic therapy) between February 2021 and May 2025 were included. Assessments included tumor response per RECIST 1.1, progression-free survival, overall survival, and adverse events graded per the National Cancer Institute Common Toxicity Criteria v5.0.ResultsThe median age was 80 years. The objective response rate was 45.9% (28/61), and the disease control rate was 85.2%. After a median follow-up of 16.7 months, the median progression-free survival was 12.7 months (95% CI: 6.9-17.1), and the median overall survival was 17.7 months (95% CI: 10.7-22.8). Both progression-free survival and overall survival significantly differed among response groups (log-rank p < 0.0001). Treatment was generally tolerable. Any-grade immune-related adverse events occurred in 39.1% of patients, with grade ≥3 events in 1.6%. Non-immune toxicities were common (any grade 93.1%; grade ≥3 in 14.7%), primarily hematologic.ConclusionIn this real-world cohort, first-line immunotherapy demonstrated promising efficacy and a manageable safety profile in patients aged ≥75 years with advanced esophageal squamous cell carcinoma. These findings provide valuable preliminary evidence supporting the use of immune checkpoint inhibitors in this understudied population and highlight the need for prospective validation to optimize therapeutic strategies.

BackgroundImmune checkpoint inhibitors (ICIs) have emerged as a pivotal treatment for advanced esophageal squamous cell carcinoma (ESCC). However, their efficacy can significantly differ among patients, highlighting the need for reliable prognostic markers to enhance treatment outcomes. Lactate dehydrogenase (LDH) plays a key regulatory role in the complex relationship between cancer metabolism and the immune system, suggesting that monitoring LDH levels may provide valuable insights into treatment efficacy and inform personalized therapeutic strategies for advanced ESCC.ObjectiveThis study aimed to explore the prognostic significance of dynamic changes in LDH levels during ICI therapy in predicting treatment outcomes.MethodsWe retrospectively analyzed the clinical data of 126 patients with advanced ESCC who received first-line ICI therapy at the Department of Radiation Oncology, Cancer Center, Shandong Provincial Hospital, between April 2018 and November 2022. Serum LDH levels were measured after every 3 cycles of combined immunotherapy and chemotherapy. Receiver operating characteristic curve analysis determined the optimal LDH reduction threshold. Kaplan-Meier survival curves and Cox regression models assessed progression-free survival (PFS) and overall survival.ResultsAmong the 126 patients, 55 (43.6%) were classified into the LDH-increased group, while 71 (56.4%) belonged to the LDH-decreased group. Within the LDH-increased group, 78.2% (43/55) of the patients were male, compared to 90.1% (64/71) in the LDH-decreased group. The median age of patients in the LDH-increased group was 59 (range 55‐68) years, whereas the median age in the LDH-decreased group was 65 (range 58‐65) years. LDH decrease following first-line ICI therapy was associated with improved outcomes compared to LDH increases (median PFS 13.4, IQR 8.1‐24.3 mo vs median 10.8, IQR 4.8‐20.6 mo; P= .03). Patients with a posttreatment LDH decrease of more than 14.4% had a median PFS of 11.1 (IQR 7.2‐24.3) months, whereas those with an LDH decrease between 0% and 14.4% had a median PFS of 21.7 (IQR 9.4‐34.5) months. Conversely, an increase in LDH resulted in a median PFS of 10.8 (IQR 4.8‐20.6) months. Patients with tumor reduction exhibited a significantly greater decrease in LDH levels compared with those without tumor reduction (P<.001). Multivariate analysis identified LDH decrease as an independent predictor of a 41% lower mortality risk (hazard ratio 0.59, 95% CI 0.36‐0.96; P=.04).ConclusionsIn patients with advanced ESCC, a decrease in serum LDH levels ranging from 0% to 14.4% after treatment initiation was significantly associated with prolonged PFS. Notably, an early decrease in LDH levels observed after 3 cycles of immunotherapy further correlated with improved clinical outcomes. These results highlight the potential of LDH as a valuable biomarker for risk stratification and personalized treatment optimization in advanced ESCC.

ObjectiveNeoadjuvant therapy is essential for locally advanced esophageal squamous cell carcinoma (ESCC), but its efficacy requires improvement. This study investigated the role of tumor-infiltrating mast cells (MCs) in treatment response and prognosis.MethodsAn integrated approach was employed, combining single-cell RNA sequencing of paired specimens from one ESCC patient pre- and post-neoadjuvant therapy, immunofluorescence analysis of a retrospective cohort of 68 treatment-naïve ESCC surgical specimens, bioinformatics analysis of public datasets, and in vitro mast cell activation assays.ResultsSingle-cell sequencing revealed a post-therapy increase in the proportion of MCs among immune cells (4% to 12%), alongside an enriched inflammatory gene profile. In the cohort of 68 patients, higher MC density was associated with smaller tumor diameter (Pearson r = −0.32, p=0.007) and significantly better overall survival (36 vs 23.5 months, p=0.038). No such correlations were found for macrophages or CD8+ T cells. Bioinformatic analysis linked MCs to extracellular matrix and vascular smooth muscle regulation. Critically, high MC density combined with low desmoplasia or fibrosis identified patients with the most favorable prognosis. Phenotypically, MCs were predominantly non-degranulated in situ. In vitro, LPS activation (a non-degranulating signal) significantly upregulated CCL19 and other chemokines in mast cells. Furthermore, LPS was detected in the tumor stroma of 47.1% (32/68) of patients but not in normal mucosa.ConclusionThe findings demonstrate that tumor-infiltrating MCs are associated with enhanced efficacy of neoadjuvant therapy and improved survival in ESCC. The mechanism may involve LPS-induced, non-degranulatory MC activation that modulates the desmoplastic microenvironment. Targeting this axis presents a promising strategy for ESCC treatment.

PurposeChemoradiotherapy (CRT) combined with anti-PD-1 for locally advanced esophageal squamous cell carcinoma (ESCC) has shown promising efficacy but lack the predictive biomarkers to identify patients who could benefit from this therapy. The predictive value of serum cytokines in ESCC patients remains unclear. We aimed to identify cytokine-based biomarkers for treatment response and survival in this setting.Experimental DesignExploratory analyses were conducted on 81 ESCC patients from two phase II trials treated with CRT plus toripalimab, with validation in an independent prospective cohort (n=61). Nineteen serum cytokines were assessed at baseline, during, and post-CRT plus anti-PD-1 antibody. A cytokine-based risk score model (CYTOscore) was constructed. Multi-omics profiling including RNA-seq, WES, and spatial transcriptomics were performed to explore potential differences in tumor microenvironments.ResultsCox analyses identified Interleukin-8 (IL-8), C-C motif chemokine ligand 3 (CCL3), and C-C motif chemokine ligand 4 (CCL4) as potential biomarkers and were used to constructed the CYTOscore. Patients stratified by baseline CYTOscore showed significantly longer OS (HR, 0.31; 95%CI, 0.16-0.62; p= 0.00045) and PFS (HR, 0.33; 95%CI, 0.17-0.62; p= 0.00036) in the low-risk group, which also had higher complete response (CR) rates (66% vs 35%, p=0.014). These finding were next validated in the external cohort, with the low-risk group demonstrating higher CR rates (66% vs 27%, p=0.039) and longer OS (HR 0.30, 95% CI 0.09-0.99, p=0.045). A nomogram incorporating baseline CYTOscore and clinical characteristics showed promising predictive accuracy in 1-, 2-, and 3-year OS (AUC=0.77, 0.78, and 0.76). Multi-omics analysis revealed enriched interferon-γ/α signaling in B cells within low-risk patients.ConclusionsThe CYTOscore based on IL-8, CCL3, and CCL4 effectively predicts treatment response and survival in ESCC patients receiving CRT plus anti-PD-1 antibody.