Gut · 2026
Alleviated T cell exhaustion and SLC1A3-mediated stroma-remodelling dictate chemoimmunotherapy efficacy in oesophageal squamous cell carcinoma.
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Xiang Shujing, Chen Yanxing, Wang Chaoye, Wang Min, He Ye, Liu Zhichao, Zhang Jin-Ling, Yang Lu-Ping, Wei Yun-Fu, Wu Qi-Nian, Wang Zi-Xian, Xi Shao-Yan, Li Zhigang, Zhao Qi, Xu Rui-Hua, Wang Feng
Аннотация
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.
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.