**Background:** Malignant pleural mesothelioma (MPM) is an aggressive solid tumor. While inflammatory and nutritional parameters such as neutrophil-to-lymphocyte ratio (NLR), prognostic nutritional index (PNI), and C-reactive protein-to-albumin ratio have been reported as prognostic factors in various malignancies, their relationship with surgical outcomes in MPM and with PD-L1 expression in the tumor microenvironment (TME) remains unclear. This study aimed to evaluate the relationship between five preoperative inflammatory/nutritional parameters and PD-L1 expression, and to assess their prognostic impact in MPM patients undergoing extrapleural pneumonectomy (EPP).
**Methods:** This retrospective, single-center study included 61 consecutive MPM patients who underwent EPP and achieved macroscopic complete resection between June 2006 and March 2020 at the National Hospital Organization Yamaguchi Ube Medical Center. Preoperative laboratory data (within 7 days before EPP) were used to calculate NLR (neutrophil count/lymphocyte count), PNI (10 × serum albumin + 0.005 × lymphocyte count), C/NLR (CRP/NLR), PLR (platelet count/lymphocyte count), and LMR (lymphocyte count/monocyte count). PD-L1 expression was assessed by immunohistochemistry using the SP142 antibody on surgically resected tissues, scored separately for tumor cells (PD-L1 TC) and immune cells (PD-L1 IC). Optimal cutoff values were determined by ROC curves predicting 5-year OS. Survival analysis used Kaplan-Meier methods with log-rank tests, and Cox proportional hazards models were used for multivariate analysis.
**Key Results:** The mean values were: NLR 2.5 (range 1.1–5.7), PNI 45.1 (29.9–64.5), C/NLR 4.20 (0.01–32.58), PLR 184.9 (62.2–436.3), and LMR 4.5 (1.2–10.3). Optimal cutoff values were: NLR 2.850, PNI 45.150, C/NLR 0.955, PLR 167.1, and LMR 5.15. PD-L1 TC score inversely correlated with PNI (Spearman's rs = 0.067, p = 0.044) and LMR (rs = 0.048, p = 0.009). PD-L1 IC score positively correlated with platelet count (rs = 0.068, p = 0.043), NLR (rs = 0.110, p = 0.009), and PLR (rs = 0.119, p = 0.006), and inversely correlated with albumin (rs = 0.081, p = 0.026), PNI (rs = 0.122, p = 0.006), and LMR (rs = 0.090, p = 0.019). Kaplan-Meier analysis showed high NLR (>2.850) was significantly associated with poor prognosis (HR 2.628, CI: 1.762–7.544, p = 0.0007), high C/NLR (>0.955) with poor prognosis (HR 2.122, CI: 1.266–4.368, p = 0.008), and high PNI (>45.150) with good prognosis (HR 0.524, CI: 0.277–0.908, p = 0.025). Multivariate Cox regression analysis identified NLR as an independent predictor of 5-year OS (HR 2.062, CI: 1.054–4.031, p = 0.034), while PNI, C/NLR, PLR, and LMR were not independent predictors.
**Clinical Implications:** This study demonstrates that preoperative NLR is an independent prognostic factor for 5-year OS in MPM patients undergoing EPP. As NLR is a simple, inexpensive, and non-invasive blood test, it could serve as a practical tool for preoperative risk stratification and surgical decision-making. The correlations between inflammatory/nutritional parameters and PD-L1 expression suggest a biological link between systemic inflammation, nutritional status, and the immune microenvironment in MPM. However, the small sample size (n = 61) and single-center retrospective design are limitations. Further larger studies are needed to validate NLR as a definitive prognostic marker and to clarify the clinical utility of combining inflammatory/nutritional parameters with PD-L1 expression for personalized treatment strategies in MPM.