Multi-omics analysis identifies a major histocompatibility complex class II-associated antigen-presenting cancer-associated fibroblast-like state linked to the nuclear factor erythroid 2-related factor 2-karyopherin subunit beta 1 axis in nonsmall cell lung cancer.

To define the transcriptional features, spatial distribution, and immune-related properties of an antigen-presenting cancer-associated fibroblast (CAF)-like state in nonsmall cell lung cancer (NSCLC), and to evaluate its relationship with the nuclear factor erythroid 2-related factor 2 (NRF2)-karyopherin subunit beta 1 (KPNB1) axis, multi-omics analyses integrating single-cell RNA sequencing, spatial transcriptomics, and bulk transcriptomic data were performed. Functional validation used primary CAFs from patients with NSCLC, including NRF2 perturbation, KPNB1 knockdown, T-cell co-culture assays, and an orthotopic murine lung cancer model treated with antiprogrammed cell death protein 1 (anti-PD-1)-based combinations. A major histocompatibility complex class II (MHC-II)-associated antigen-presenting CAF-like (apCAF-like) state was identified in NSCLC. It showed increased antigen-presentation-related molecules, limited co-stimulatory molecule expression, and inferred communication involving MHC-II, transforming growth factor-β, and C-X-C motif chemokine ligand pathways. Higher KPNB1 expression was associated with poorer survival, lower immune infiltration, and lower ImmuneScore. In primary CAFs, NRF2 activation increased KPNB1 and reduced class II MHC transactivator, major histocompatibility complex class II DR alpha (HLA-DRA), and MHC-II-related signals, whereas NRF2 inhibition showed the opposite pattern. KPNB1-low CAFs enhanced T-cell activation and cytokine release, and KPNB1 knockdown enriched antigen-presentation-related transcriptional programs. In vivo, inhibition of the NRF2-KPNB1 axis enhanced response to anti-PD-1. NSCLC contains an MHC-II-associated apCAF-like state linked to the NRF2-KPNB1 axis and altered response to PD-1 blockade.