Integrated Spatial Immune Phenotyping Identifies a Suppressive-infiltrated High-risk Subgroup in Esophageal Squamous Cell Carcinoma

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Background/Aim: Esophageal squamous cell carcinoma (ESCC) exhibits substantial heterogeneity in its tumor immune microenvironment (TIME). We aimed to establish an integrated spatial immune phenotyping framework incorporating immune infiltration, spatial distribution, and suppressive-effector immune balance. Patients and Methods: A total of 139 patients with surgically resected ESCC were retrospectively analyzed, including a discovery cohort (n=89) and an external validation cohort (n=50). Whole-slide histopathological evaluation and immunohistochemistry were used to assess spatial immune-cell infiltration. Tumors were classified according to total tumor-infiltrating lymphocyte (TIL) level, the intratumoral-to-stromal TIL ratio, and stromal suppressive-to-effector immune balance. TCGA-ESCA transcriptomic data were analyzed to characterize the identified phenotypes. Results: Stromal TILs significantly exceeded intratumoral TILs (p<0.001). Increased intratumoral immune infiltration and enrichment of suppressive immune-cell populations were associated with aggressive clinicopathological features. Four immune phenotypes were identified: immune-cold, immune-excluded, CD8-effector infiltrated, and suppressive-infiltrated. The suppressive-infiltrated phenotype showed the poorest overall survival in both the discovery (p=0.010) and validation cohorts (p=0.008). In the pooled cohort, Type IV status remained independently associated with worse overall survival after adjustment for major clinicopathological factors [hazard ratio (HR)=2.64, 95% confidence interval (CI)=1.20-5.79, p=0.015]. Adding Type IV status improved prognostic performance (C-index: 0.650 to 0.673; likelihood-ratio test, p=0.018). Transcriptomic analyses demonstrated increased immune checkpoint activity, T-cell exhaustion, and stromal activation signatures in the suppressive-infiltrated phenotype (all p<0.05). Conclusion: Integrated assessment of immune infiltration, spatial distribution, and suppressive-effector balance identified clinically distinct immune phenotypes in ESCC. The suppressive-infiltrated phenotype represents a high-risk immune microenvironmental subgroup independently associated with poor survival.

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