IGHG1⁺ plasma cells define an NF-κB-driven inflammatory program that shapes T-cell immunity and immunotherapy...

The efficacy of immune checkpoint blockade (ICB) in colorectal cancer (CRC) is constrained by marked heterogeneity in the tumor microenvironment (TME). Although B cells and tertiary lymphoid structures (TLS) have emerged as important determinants of anti-tumor immunity, the functional diversity of plasma-cell subsets in CRC immunotherapy remains insufficiently understood.

We performed an integrative analysis combining public single-cell RNA sequencing data, validation in independent bulk transcriptomic immunotherapy cohorts, and in vitro and in vivo functional experiments. Tumor-infiltrating B-cell subsets were characterized at single-cell resolution, and an IGHG1⁺ plasma-cell-associated signature was constructed for external validation.

We identified an IGHG1⁺ plasma-cell subset that was preferentially enriched in tumors from patients with favorable immunotherapy response. Within this compartment, High-IGHG1 plasma cells displayed a transcriptional program associated with antigen presentation, inflammatory signaling, and NF-κB pathway activation. Tumors enriched for this population showed coordinated expansion of activated T-cell states, particularly cytotoxic CD8⁺ subsets. An IGHG1⁺ plasma-cell signature derived from these findings predicted immunotherapy response across multiple independent cohorts and was associated with prolonged progression-free survival in external datasets. In transcriptome bulk CRC cohorts, the signature correlated with immune activation, chemokine signaling, and TNF-α/NF-κB-related inflammatory pathways. Functional experiments further supported a role for NF-κB signaling in maintaining the inflammatory program of IGHG1⁺ B cells and in promoting a tumor microenvironment favorable to CD8⁺ T-cell cytotoxicity.

Our study identifies an NF-κB-associated IGHG1⁺ plasma-cell state linked to T-cell activation and improved immunotherapy response in CRC. These findings expand the current understanding of B-cell heterogeneity in tumor immunity and support the potential value of IGHG1⁺ plasma cells as both a biomarker and a mechanistic target in precision immunotherapy.