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

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.