# Exploring the Link Between Stress-Induced Naive T-Cells and Esophageal Squamous Cell Carcinoma Risk: A Multi-Omics Investigation

## TL;DR

This study finds that higher numbers of naive T-cells are linked to increased risk of esophageal cancer, due to their impaired function in the tumor environment.

## Contribution

The study identifies naive T-cell abundance as a novel causal risk factor for esophageal squamous cell carcinoma through multi-omics analysis.

## Key findings

- Naive T-cell abundance shows a positive causal effect on esophageal cancer risk (OR 1.14).
- Tumor-infiltrating naive T-cells exhibit metabolic quiescence and suppressed differentiation.
- Impaired T-cell function correlates with immune evasion in esophageal carcinogenesis.

## Abstract

The dynamic crosstalk between immunoregulatory constituents and neoplastic evolution underscores the centrality of immune homeostasis in oncogenesis. naïve T-lymphocytes, as primary architects of adaptive immunity, are critically implicated in antitumor responses. Deciphering their mechanistic linkage to esophageal carcinogenesis is vital for elucidating immune-mediated susceptibility and malignant progression. This investigation synergizes Mendelian randomization with single-cell multi-omics to dissect this pathobiological nexus.

A bidirectional two-sample Mendelian randomization framework was deployed to infer causal associations between leukocyte subsets and esophageal squamous cell carcinoma. Genome-wide summary statistics were analyzed from 476,306 malignancy cases and immunophenotypic data spanning 731 European-ancestry participants. Complementary single-cell transcriptional profiling of tumor-adjacent dyads provided mechanistic validation.

Inverse variance-weighted regression demonstrated a positive causal effect of naive T-cell abundance on esophageal cancer risk (odds ratio 1.14; 95% confidence interval 1.03–1.27; P = 0.021). Single-cell analyses unveiled tumor-infiltrating naïve T-lymphocytes in a metabolically quiescent state with suppressed effector differentiation trajectories, indicative of microenvironment-driven anergy. This functional impairment correlated with compromised immunoediting capacity, potentiating neoplastic immune evasion mechanisms.

Our integrative analysis establishes naïve T-cell abundance as a novel causal risk factor for esophageal squamous cell carcinoma, mediated through metabolic silencing and differentiation blockade within the tumor niche. These findings redefine the immunopathogenic paradigm of esophageal carcinogenesis, suggesting that therapeutic strategies targeting T-cell metabolic reprogramming may disrupt immune-evasion pathways. The demonstrated synergy between population-level genetic inference and single-cell mechanistic validation provides a transformative framework for cancer immunology research.

The online version contains supplementary material available at 10.1245/s10434-025-18541-w.