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

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. 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. 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. 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.