Dynamic evolution of NK cells and immune remodeling mediated by CRS + HIPEC: prognostic mechanisms and therapeutic...

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). 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.

This study retrospectively enrolled 80 newly diagnosed MPM patients (preoperative group) and 64 patients who underwent CRS + HIPEC (postoperative group). The level of NK cells (CD3^-CD56^dimCD16⁺) 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.

41 patients (51.3%) exhibited decreased NK cell levels preoperatively, which were significantly associated with an increased risk of thrombosis (P = 0.023), intraoperative plasma transfusion (P = 0.004), and prolonged hospitalization duration (P = 0.023). Postoperative dynamic changes in NK cell levels were found to correlate with Karnofsky performance scale (KPS) scores (P = 0.048) and elevated levels of IL-4, IL-5, IL-6, and IL-8 (P < 0.05). Multivariate analysis revealed that the volume of intraoperative plasma transfusion was an independent correlated factor for preoperative NK cell reduction (P = 0.013), while a low KPS score was an independent predictor of postoperative NK cell decline (P = 0.048). Survival analysis indicated that a high perioperative stress score (PSS) (P = 0.015), lymph node metastasis (P = 0.015), significant intraoperative blood loss (P = 0.013), low preoperative CD8⁺ T cell levels (P = 0.001), and reduced postoperative IL-17 expression (P = 0.013) were independent adverse prognostic factors for overall survival (OS). Furthermore, the dynamic NK cell recovery model demonstrated that baseline NK cell levels, peritoneal cancer index (PCI), CD8⁺ T cell status, and postoperative recovery time all significantly influenced the immune remodeling process (all P < 0.001).

Preoperative NK depletion correlated with thrombosis and surgical risks, while postoperative NK recovery was influenced by KPS, specific cytokines (IL-4/5/6/8), and was significantly enhanced after CRS + HIPEC.