Objective To investigates the role of serum interleukin-6 (IL-6) and tumor necrosis factor-α(TNF-α) levels as prognostic biomarkers in patients receiving First-Line Platinum-Based Chemotherapy Combined with Immunotherapy for NSCLC.Methods A retrospective analysis was conducted on the data of 108 patients with locally advanced NSCLC who received first-line platinum-based chemotherapy combined with immunotherapy at Lianyungang Second People's Hospital from January 2022 to June 2025. According to the RECIST 1.1 criteria, patients with complete response (CR) and partial response (PR) were included in the objective response group (ORR group), while those with stable disease (SD) and progressive disease (PD) were included in the non-objective response group (non-ORR group). The levels of serum IL-6 and TNF-α and clinical characteristics were compared between the two groups.Identification of Independent Factors Affecting Treatment Efficacy via Logistic Regression Analysis, and the predictive cutoff values were determined through ROC curves.Results The baseline IL-6 and TNF-α and the post-treatment IL-6 level in the non-ORR group were significantly higher than those in the ORR group (P < 0.05), and the proportion of patients with low albumin levels and ECOG score of 3 was also higher (P < 0.05). Multivariate analysis revealed that an elevated ECOG performance status, high baseline TNF-α levels, and elevated post-treatment IL-6 levels were independent risk factors for non-response to treatment. The ROC curves indicated that post-treatment IL-6 (AUC = 0.773, 95% CI 0.641–0.904) and baseline TNF-α (AUC = 0.656, 95% CI 0.508–0.804) had significant predictive efficacy, with the optimal cutoff values being 5.81 pg/ml and 1.9 pg/ml, respectively.Conclusion High baseline TNF-α levels and high post-treatment IL-6 levels are significantly associated with poor chemo-immunotherapy efficacy. Dynamic monitoring of these two factors may provide a reference for assessing clinical efficacy and guiding individualized treatment strategies.