Alleviated T cell exhaustion and SLC1A3-mediated stroma-remodelling dictate chemoimmunotherapy efficacy in oesophageal squamous cell carcinoma

Abstract

Background: Combining chemotherapy with anti-programmed cell death protein-1 (PD-1) improves clinical outcomes in oesophageal squamous cell carcinoma (ESCC), yet the underlying synergistic mechanism remains obscured. Moreover, 30-50% of patients still derive no therapeutic benefit from the combination strategy, highlighting the need to decipher and overcome resistance.

Objective: We sought to investigate the mechanisms by which chemotherapy augments the responses to immune checkpoint blockade and elucidate the factors contributing to persistent resistance in non-responding patients.

Design: We designed a systematic investigation involving longitudinal sampling of ESCC tissues both from patients treated with chemotherapy plus anti-PD-1 and anti-PD-1 monotherapy. The tumour microenvironment (TME) was then comprehensively characterised using single-cell transcriptomics, T cell receptor repertoire analysis, multiplex immunohistochemistry and murine models.

Results: We demonstrated that combination therapy exerted superior antitumour efficacy by mitigating immune checkpoint engagements (TIGIT-NECTIN2 and NECTIN1-CD96) between epithelial-stress tumour cells and CD8⁺ T cells, thereby preventing T cells from exhaustion and boosting vitality. In non-responders, we identified a subset of tumour cells with high SLC1A3 expression, which localised at the tumour boundary and interacted with COL1A1⁺ myofibroblastic cancer-associated fibroblasts, inducing an extracellular matrix-enriched TME that hindered the infiltration of CD8⁺ T cells. Inhibiting SLC1A3 significantly enhanced the efficacy of chemotherapy plus anti-PD-1, underscoring its potential as a therapeutic target.

Conclusion: This study elucidates the synergistic mechanisms and identifies key resistance pathways underlying chemo-immunotherapy combinations in patients with ESCC, providing a scientific basis for refining future combination therapeutic regimens.

Keywords: EPITHELIAL CELLS; IMMUNOTHERAPY; OESOPHAGEAL CANCER; SINGLE-CELL ANALYSIS.