The IFN-I-DUSP2-NFAT axis Limits Tumor Remodeling and Immunotherapy Response in Lung Cancer

Type I interferons (IFN-I) exert context-dependent effects in tumor microenvironment (TME), but their role in shaping immunotherapy response remains unclear. Here, we performed single-cell RNA sequencing of lung squamous cell carcinoma (LUSC) samples collected before and after immune checkpoint blockade (ICB), stratified by treatment outcome. In responders, ICB induced B cell and T follicular helper (Tfh) cell expansion, promoting the formation of tertiary lymphoid structure (TLS)-like niche. By contrast, non-responders exhibited sustained IFN-I signaling and accumulation of CD36⁺ SPP1⁺ tumor-associated macrophages (TAMs), which secreted IFN-I and disrupted lymphoid aggregation. At baseline, aberrant NFAT signaling in T cells marked a dysfunctional state. Mechanistically, IFN-I upregulated the phosphatase DUSP2 in pre-exhausted T cells, which dephosphorylated NFAT and promoted its nuclear localization. Nuclear NFAT transactivated genes encoding inhibitory receptors to reinforce T cell exhaustion. Deletion of Dusp2 restored CD8+ T cell function and Tfh-B cell interaction, improving response to PD-1 blockade. These findings identify a pathogenic IFN-I-DUSP2-NFAT axis that constrains immunotherapy efficacy in LUSC. Study of tumor infiltration lymphocytes from LLC-bearing tumors in WT and Dusp2−/− mice using 10x scRNA-seq technologies.