Dynamic evolution of NK cells and immune remodeling mediated by CRS+HIPEC: prognostic mechanisms and therapeutic implications for malignant peritoneal mesothelioma

Background: Malignant peritoneal mesothelioma (MPM) is a highly aggressive peritoneal malignancy with a significant recurrence rate following cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Thus, there is an urgent need to investigate novel therapeutic strategies for MPM. Natural killer (NK) cells exhibit rapid responsiveness in anti-tumor immunity; however, NK cells' dynamic evolution and clinical significance in MPM remain unclear. Methods: This study retrospectively enrolled 80 newly diagnosed MPM patients (preoperative group) and 64 patients who underwent CRS+HIPEC (postoperative group). The frequency of NK cells (CD3 ^- CD56 ^dim CD16 ⁺ ) in peripheral blood was quantified using flow cytometry. Univariate and multivariate regression analyses were performed to evaluate the association between NK cell counts and clinicopathological characteristics, intraoperative events, and prognosis. A multivariate prediction model for NK cell recovery was established. Results: Preoperative NK cell reduction was observed in 41 patients (51.3%), and this phenomenon was significantly associated with preoperative thrombosis ( P = 0.023), a high intraoperative plasma infusion volume ( P = 0.004), prolonged hospital stay ( P = 0.023), decreased total lymphocyte count ( P = 0.011), and an elevated CD4 ⁺ /CD8 ⁺ T cell ratio ( P = 0.018). The median NK cell count increased significantly to 278 cells/μL postoperatively. Postoperative NK cell reduction occurred in 20 cases (31.3%), which was independently correlated with lower Karnofsky performance scale (KPS) scores ( P = 0.048), and higher expression levels of interleukins IL-4 ( P = 0.020), IL-5 ( P = 0.007), IL-6 ( P = 0.016), and IL-8 ( P = 0.018). Elevated levels of IL-2 ( P = 0.019) and IL-4 ( P = 0.007) were identified as independent factors contributing to NK cell depletion following surgery. Survival analysis revealed that a high perioperative stress score (PSS) ( P = 0.015), lymph node metastasis ( P = 0.015), intraoperative blood loss ( P = 0.013), low preoperative CD8⁺T cell levels ( P = 0.001), and low postoperative IL-17 expression levels ( P = 0.013) were independent adverse predictors of overall survival (OS). Patients with higher preoperative NK cell levels exhibited a tendency toward longer OS. Furthermore, the dynamic NK recovery model demonstrated that baseline NK cell levels ( P < 0.001), peritoneal cancer index (PCI) ( P < 0.001), CD8⁺T cell status ( P < 0.001), and postoperative recovery time ( P < 0.001) all influenced the immune remodeling process. Conclusions: This study represents the first systematic investigation into the spatiotemporal dynamic characteristics of NK cells in MPM patients. More than half of MPM patients experienced preoperative NK cell depletion, which CRS+HIPEC could effectively reverse. The NK cell count may serve as a dynamic biomarker for tumor burden and immunosuppressive microenvironment assessment, with its preoperative elevation potentially improving prognosis. Targeting the IL-2/IL-4 pathway alone or in combination with CD8⁺ T cells may offer a novel strategy for MPM immunotherapy.