Background: Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma (LUAD) typically demonstrates limited response to neoadjuvant immunotherapy (NIT). Elucidating the immune determinants that differentiate responders from non-responders was critical for optimizing immunotherapy strategies. This study aimed to characterize the tumour microenvironment features of KRAS-mutant LUAD following neoadjuvant programmed death protein 1 (PD-1) inhibitor therapy by integrating clinical outcomes with single-cell RNA sequencing (scRNA-seq).
Methods: A total of 143 patients with resectable LUAD were consecutively enrolled in this study, including 106 cases in the KRAS-wildtype cohort and 37 cases in the KRAS-mutant cohort. We systematically compared the pathological response rates, survival outcomes and recurrence patterns between the two cohorts. We performed scRNA-seq on tumour specimens from 234 real-world patients with non-small cell lung cancer. From this cohort, 48 LUAD cases were identified and stratified by KRAS mutation status (13 KRAS-mutant and 35 KRAS-wildtype patients). Cellular compositions, transcriptional features and intercellular communication networks were analysed.
Results: Clinical analysis revealed that the KRAS-mutant group exhibited significantly poorer pathological responses (p = .032) and inferior long-term survival compared to the KRAS-wildtype group. We identified an immunosuppressive tumour necrosis factor receptor superfamily member 4 (TNFRSF4)-expressing regulatory T-cell (CD4T_Treg_TNFRSF4) subset enriched in non-responders, whereas responders showed increased frequencies of T helper 1 cells (Th1 cells) and a previously unrecognized exhausted-like B-cell state (Bex). Bex cells displayed impaired metabolic activity yet retained antigen presentation potential and showed extensive cellular interactions with Th1 cells, suggesting a supportive role in Th1-mediated antitumour immunity.
Conclusion: KRAS-mutant patients exhibited significantly poorer pathological responses, and KRAS-mutant status may independently predict survival outcomes after NIT in LUAD patients. Additionally, our study unveiled the cellular and molecular architecture underlying differential responses to NIT in KRAS-mutant LUAD, emphasizing the opposing roles of immunosuppressive Tregs and synergistic Bex–Th1 networks.
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2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
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