Resistance to anti-LAG-3 plus anti-PD-1 therapy in head and neck cancer is mediated by Sox9+ tumor cells interaction with Fpr1+ neutrophils

Xiaochen Wang, Maosheng Cheng, Shuang Chen, Caihua Zhang, Rongsong Ling, Shuqing Qiu, Ke Chen, Bin Zhou (), Qiuli Li (), Wenbin Lei () and Demeng Chen ()
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Xiaochen Wang: Sun Yat-sen University
Maosheng Cheng: Sun Yat-sen University
Shuang Chen: Sun Yat-sen University
Caihua Zhang: Sun Yat-sen University
Rongsong Ling: Sun Yat-sen University
Shuqing Qiu: Sun Yat-sen University
Ke Chen: Sun Yat-sen University
Bin Zhou: University of Chinese Academy of Sciences
Qiuli Li: Sun Yat-sen University Cancer Center
Wenbin Lei: Sun Yat-sen University
Demeng Chen: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Relatlimab and nivolumab combination therapy shows significant efficacy in treating various types of cancer. Current research on the molecular mechanisms of this treatment is abundant, but in-depth investigations into post-treatment resistance remain notably lacking. In this study, we identify significant enrichment of SRY (sex determining region Y)-box 9 (Sox9)+ tumor cells in resistant samples using single cell RNA sequencing (scRNAseq) in a head and neck squamous cell carcinoma (HNSCC) mouse model. In addition, Sox9 directly regulates the expression of annexin A1 (Anxa1), mediating apoptosis of formyl peptide receptor 1 (Fpr1)+ neutrophils through the Anxa1-Fpr1 axis, which promotes mitochondrial fission, inhibits mitophagy by downregulating BCL2/adenovirus E1B interacting protein 3 (Bnip3) expression and ultimately prevents the accumulation of neutrophils in tumor tissues. The reduction of Fpr1+ neutrophils impairs the infiltration and tumor cell-killing ability of cytotoxic Cd8 T and γδT cells within the tumor microenvironment, thereby leading to the development of resistance to the combination therapy. We further validate these findings using various transgenic mouse models. Overall, this study comprehensively explains the mechanisms underlying resistance to the anti-LAG-3 plus anti-PD-1 combination therapy and identifies potential therapeutic targets to overcome this resistance.

Date: 2025
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DOI: 10.1038/s41467-025-59050-4

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