The phosphatase DUSP2 constrains lymphoid remodeling and immunotherapy response in lung squamous carcinoma.

Although immune checkpoint blockade (ICB), including in combination with neoadjuvant regimens, has shown encouraging efficacy in lung cancer, a substantial fraction of patients remains resistant, and the underlying mechanisms are not fully understood. Here, we performed single-cell RNA sequencing of lung squamous cell carcinoma (LUSC) samples collected before and after ICB, stratified by therapeutic outcome. In responders, ICB promoted the expansion of B cells and T follicular helper (Tfh) cells, supporting the formation of tertiary lymphoid structure. In contrast, non-responders exhibited persistent type I interferon (IFN-I) signaling driven by CD36+SPP1+ tumor-associated macrophages, which disrupted lymphoid organization. At baseline, dysfunctional T cells were characterized by aberrant nuclear factor of activated T cells (NFAT) signaling. Mechanistically, IFN-I induced the expression of the phosphatase dual-specificity phosphatase 2 (DUSP2) in pre-exhausted T cells, promoting NFAT dephosphorylation and nuclear accumulation. Nuclear NFAT upregulated inhibitory receptors and antagonized Bcl6-dependent transcriptional programs, thereby reinforcing T cell exhaustion and impairing Tfh differentiation. Genetic ablation of Dusp2 restored CD8+ T cell function and Tfh-B cell interaction, enhancing responsiveness to ICB. These findings identify a pathogenic IFN-I-DUSP2-NFAT axis that limits immunotherapy efficacy in LUSC.