The multidimensional regulatory network of the PD‑1/PD‑L1 axis in the esophageal squamous cell carcinoma microenvironment: Implications for novel combination therapies and precision immunotherapy (Review).

Esophageal cancer is a highly prevalent malignancy worldwide. Although immunotherapy, particularly programmed cell death‑1/programmed cell death ligand 1 (PD‑1/PD‑L1) inhibitors, has notably improved patient outcomes, the overall response rate remains limited. This limited efficacy is largely attributed to complex immunosuppressive networks within the tumor microenvironment (TME). The present review systematically dissects the multifaceted regulatory mechanisms of the PD‑1/PD‑L1 signaling axis in the TME of esophageal squamous cell carcinoma (ESCC), and its impact on immunotherapeutic efficacy. Emerging evidence indicates that multiple immunosuppressive mechanisms within the TME shape the response to immune checkpoint inhibitors: Regulatory T cells enhance immunosuppression via the TGF‑β‑PD‑1/PD‑L1 axis; IL‑6/STAT3 signaling upregulates PD‑L1 expression and mitochondrial remodeling and amino acid network regulation exacerbate T cell exhaustion. Meanwhile, tertiary lymphoid structure (TLS) maturation is positively associated with clinical prognosis by promoting tissue‑resident memory T cell activation and enhancing antitumor immunity. By contrast, the predictive value of tumor mutational burden (TMB) is constrained by TME heterogeneity. Emerging strategies highlight the predictive potential of TLS maturity and TMB, although the predictive relevance of TMB in ESCC remains inconsistent. Combination approaches show promise in reversing T/natural killer cell exhaustion and remodeling immunosuppressive TMEs. Future research should combine multi‑omics data with clinical information to develop personalized immunotherapy models for ESCC.