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Peer-reviewedCC BY-NC-NDRespiratory research

Serum cytokine profiles in a real-world cohort of KRAS-Mutant NSCLC and its therapeutic implications for subtype-specific immunotherapy.

  • Bo Yuan1
  • Yuanyi Zhang1
  • Xiao Li1
  • YuJiao Dong1
  • Xiaopeng An1
  • Tong Jiao1
  • Cai Zhang1
  • Yang Chen1
  • Jie Shi1
  • Shiqi Wu2
  • Shuanying Yang3
  1. 1Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  2. 2Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  3. 3Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi'an, Shaanxi, 710004, China. [email protected].
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Abstract

Background

KRAS‑mutant non‑small cell lung cancer (NSCLC) is heterogeneous, but the subtype‑specific profiles of systemic cytokines and their impact on immunotherapy outcomes remain unclear.Methods

This retrospective study included 139 patients with KRAS‑mutant NSCLC stratified into G12C (44.6%), G12D (21.6%), and other G12 variants (G12V/A/S/R) (33.8%). Serum levels of seven cytokines (IL‑6, IL‑8, TNF‑α, IL‑10, IL‑17, IL‑1β, IL‑4) were available for 109 patients. Associations with progression‑free survival (PFS) and overall survival (OS) were analyzed using Kaplan‑Meier and Cox regression.Results

Distinct cytokine profiles emerged across subtypes: IL‑10 was elevated in G12C, while IL‑17 was higher in G12D. In the overall ICI‑treated cohort (n = 80), elevated IL‑6, IL‑8, and TNF‑α were associated with worse PFS and OS in univariable analyses. After multivariable adjustment, only IL‑6 remained an independent unfavorable prognostic factor for PFS (adjusted HR = 2.66, p = 0.042). For OS, all three cytokines remained significant after limited adjustment (IL‑6 HR = 2.67, p = 0.050; IL‑8 HR = 5.00, p = 0.049; TNF‑α HR = 2.61, p = 0.037), but findings were exploratory due to not adjusted for multiple testing. In first‑line patients (n = 57), only IL‑6 predicted worse PFS (adjusted HR = 5.34, p = 0.002). Subgroup analysis showed that in G12C (n = 38), IL‑6 and TNF‑α were associated with worse PFS/OS, while in G12D (n = 16), IL‑17 showed a significant association with shorter PFS (log‑rank p = 0.037). No cytokine was prognostic in the G12V/A/S/R subgroup.Conclusion

These findings suggest that KRAS mutation subtypes may be associated with distinct serum cytokine profiles. IL-6 appeared as a potential subtype-independent negative prognostic factor for PFS, while IL-17 may be relevant in G12D tumors. These observations provide an early rationale for exploring subtype-specific cytokine-targeted strategies, though confirmation in larger prospective cohorts is needed.

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Cite

BibTeXRIS
BibTeX
@article{yuan2026serum,
  title = {{Serum cytokine profiles in a real-world cohort of KRAS-Mutant NSCLC and its therapeutic implications for subtype-specific immunotherapy.}},
  author = {Bo Yuan and Yuanyi Zhang and Xiao Li and YuJiao Dong and Xiaopeng An and Tong Jiao and Cai Zhang and Yang Chen and Jie Shi and Shiqi Wu and Shuanying Yang},
  journal = {Respiratory research},
  year = {2026},
  month = aug,
  doi = {10.1186/s12931-026-03858-1},
  url = {https://europepmc.org/article/MED/42958260},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Serum cytokine profiles in a real-world cohort of KRAS-Mutant NSCLC and its therapeutic implications for subtype-specific immunotherapy.
AU  - Bo Yuan
AU  - Yuanyi Zhang
AU  - Xiao Li
AU  - YuJiao Dong
AU  - Xiaopeng An
AU  - Tong Jiao
AU  - Cai Zhang
AU  - Yang Chen
AU  - Jie Shi
AU  - Shiqi Wu
AU  - Shuanying Yang
PY  - 2026
DA  - 2026/08/01
JO  - Respiratory research
DO  - 10.1186/s12931-026-03858-1
UR  - https://europepmc.org/article/MED/42958260
AB  - Background  KRAS‑mutant non‑small cell lung cancer (NSCLC) is heterogeneous, but the subtype‑specific profiles of systemic cytokines and their impact on immunotherapy outcomes remain unclear.Methods  This retrospective study included 139 patients with KRAS‑mutant NSCLC stratified into G12C (44.6%), G12D (21.6%), and other G12 variants (G12V/A/S/R) (33.8%). Serum levels of seven cytokines (IL‑6, IL‑8, TNF‑α, IL‑10, IL‑17, IL‑1β, IL‑4) were available for 109 patients. Associations with progression‑free survival (PFS) and overall survival (OS) were analyzed using Kaplan‑Meier and Cox regression.Results  Distinct cytokine profiles emerged across subtypes: IL‑10 was elevated in G12C, while IL‑17 was higher in G12D. In the overall ICI‑treated cohort (n = 80), elevated IL‑6, IL‑8, and TNF‑α were associated with worse PFS and OS in univariable analyses. After multivariable adjustment, only IL‑6 remained an independent unfavorable prognostic factor for PFS (adjusted HR = 2.66, p = 0.042). For OS, all three cytokines remained significant after limited adjustment (IL‑6 HR = 2.67, p = 0.050; IL‑8 HR = 5.00, p = 0.049; TNF‑α HR = 2.61, p = 0.037), but findings were exploratory due to not adjusted for multiple testing. In first‑line patients (n = 57), only IL‑6 predicted worse PFS (adjusted HR = 5.34, p = 0.002). Subgroup analysis showed that in G12C (n = 38), IL‑6 and TNF‑α were associated with worse PFS/OS, while in G12D (n = 16), IL‑17 showed a significant association with shorter PFS (log‑rank p = 0.037). No cytokine was prognostic in the G12V/A/S/R subgroup.Conclusion  These findings suggest that KRAS mutation subtypes may be associated with distinct serum cytokine profiles. IL-6 appeared as a potential subtype-independent negative prognostic factor for PFS, while IL-17 may be relevant in G12D tumors. These observations provide an early rationale for exploring subtype-specific cytokine-targeted strategies, though confirmation in larger prospective cohorts is needed.
SN  - 1465-9921
SN  - 1465-993X
ER  -