Precision immunotherapy in oesophageal squamous cell carcinoma: Molecular pathogenesis and checkpoint inhibitor response prediction

Table 1 Summary of predictive biomarkers for immune checkpoint inhibitor response in esophageal squamous cell carcinoma

Biomarker category	Biological basis/what is measured	General predictive value for ICI response	Status in ESCC clinical practice	Key challenges and limitations
PD-L1 expression[29]	Protein expression of programmed death-ligand 1 on tumour and/or immune cells via IHC	Higher expression (e.g., CPS ≥ 10) correlates with increased likelihood of response	Clinically established and mandated for first-line pembrolizumab-based therapy selection. Widely used in trials and practice	Significant intra-/inter-tumoural heterogeneity; lack of standardization across assays/platforms; dynamic expression; responses occur in some PD-L1 negative patients
Tumour mutational burden[31,32]	Total number of somatic mutations per megabase of tumour DNA, a proxy for neoantigen load	High TMB (≥ 10 mut/Mb) is associated with improved response and survival across multiple cancers	Emerging biomarker. Retrospective data suggests predictive value; not yet a standard for therapy selection in ESCC	Lack of standardized cutoff for ESCC; lack of prospective ESSC-specific validation for optimal cut-off; variability across sequencing panels; requires next-generation sequencing
Microsatellite instability/mismatch repair deficiency[33,34]	Genomic hypermutability due to defective DNA mismatch repair, leading to high frame-shift neoantigen burden	MSI-H/dMMR is a highly predictive pan-cancer biomarker for robust ICI response	Standard of care to test, but very rare (< 2% prevalence). Identification is critical due to high efficacy	Extremely low prevalence in ESCC limits utility for most patients; requires IHC for MMR proteins or PCR/NGS for MSI testing
Gene expression profiles/immune signatures[35,36]	Transcriptomic quantification of immune-related genes (e.g., IFN-γ signaling, cytotoxic T cell markers, antigen presentation)	A pre-existing, “T-cell inflamed” microenvironment signature correlates with better ICI outcomes	Investigational. Not used clinically but a focus of research to better define the immune contexture beyond single markers	Lack of standardized, validated assay/platform for clinical use; complexity of data interpretation; tumour heterogeneity
Circulating biomarkers (e.g., ctDNA)[37,38]	Dynamic, non-invasive measurement of tumour-derived signals in blood (e.g., ctDNA level, NLR)	Early clearance of ctDNA predicts favorable outcome. High baseline NLR may correlate with poorer outcomes	Investigational/for monitoring. ctDNA shows promise for real-time response monitoring. Not yet validated for prospective treatment decisions	Requires validation in large prospective trials; optimal timing and thresholds not defined; detection rates are significantly lower in early-stage vs. metastatic disease, limiting its utility for screening or monitoring in non-advanced settings; confounding factors for NLR

ESCC: Oesophageal squamous cell carcinoma; ICI: Immune checkpoint inhibitors; PD-L1: Programmed death-ligand 1; IHC: Immunohistochemistry; CPS: Combined positive score; TMB: Tumour mutational burden; MSI-H/dMMR: Microsatellite instability-high/Mismatch repair deficiency; PCR/NGS: Polymerase chain reaction/next-generation sequencing; NLR: Neutrophil-to-lymphocyte ratio.