TM9SF2 Reprograms Antigen Presenting Neutrophils to Overcome Immune Evasion in NSCLC [Bulk RNA-seq]

Through a surfaceome-focused CRISPR screen, we identified Tm9sf2 as a critical regulator of immune evasion in NSCLC. We demonstrate that Tm9sf2 sustains an MHC I/II-mediated antigen-presenting Il15rahigh neutrophil subset, which is essential for T cell infiltration and activation.

Mechanistically, Tm9sf2 deficiency disrupts nuclear translocation of the NuRD transcriptional repressor complex, leading to derepression of Col6a1 and its pathological hypersecretion into the tumor microenvironment. Subsequently, Col6a1 binds to the surface receptor Tlr4 on neutrophils, activating the Stat3-Socs1 axis to suppress interferon signaling and impair antigen presentation, thereby abrogating neutrophil- and T cell-mediated anti-tumor immunity.