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

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: 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.