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

Our plain-English summary of Dynamic evolution of NK cells and immune remodeling mediated by CRS + HIPEC: prognostic mechanisms and therapeutic implications for malignant peritoneal mesothelioma, by Y.T. Liu, Q.D. Zhao, X.L. Liang, et al (World Journal of Surgical Oncology, 2025).

The study

• Authors: Y.T. Liu, Q.D. Zhao, X.L. Liang, R. Ma, Y.D. Su, R. Yang, T. Wei, H.L. Wu, Y.B. Fu, Y.R. Cui, Y. Yu, B. Li, Y. Li
• Journal: World Journal of Surgical Oncology
• Published: 2025;23(1):416
• Read it: PubMed · Publisher · Free full text

Abstract

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). 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 level of NK cells (CD3-CD56dimCD16+) 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: 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).

Conclusions: 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.

© 2025. The Author(s).

In plain English

This retrospective study from Beijing looked at natural killer (NK) cells, a type of immune cell, in the blood of patients with malignant peritoneal mesothelioma treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). It did not study asbestos exposure. Between May 2023 and February 2025, 80 newly diagnosed patients were enrolled, and 64 of them also had NK counts measured about 30 days after surgery. Before surgery, 41 of 80 patients (51.3%) had low NK counts. The preoperative NK groups differed in preoperative blood clots (thrombosis), plasma transfusion volume and hospital stay. Only 3 patients had preoperative thrombosis. After surgery, NK counts rose in 60.9% of the 64 patients. NK changes were linked to performance status (KPS) and to IL-4, IL-5, IL-6 and IL-8 levels. Neither preoperative NK levels nor postoperative NK changes were significantly linked to survival. By the end of follow-up, 9 of 80 and 3 of 64 patients had died. The authors concluded that CRS + HIPEC enhanced NK cell function. They also wrote that confounding factors could not be excluded and that their analyses were exploratory, with no correction for multiple comparisons.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Single-center retrospective study of blood NK cell counts measured before and after surgery, with group comparisons, logistic and Cox regression, and a regression model of NK cell change
• Who was studied: 80 patients newly diagnosed with malignant peritoneal mesothelioma (MPM), enrolled May 2023 to February 2025 (ethics approval from Beijing Shijitan Hospital, China). 64 of them had postoperative NK assessments and formed the postoperative group. Median age was 56 (range 14 to 74); 45 were female and 35 male; 58 had epithelioid tumors.
• Exposure: No asbestos or fiber exposure was studied. The study examined blood NK cell (CD3-CD56dimCD16+) counts measured by flow cytometry within 7 days before CRS + HIPEC and about 30 days (plus or minus 5) after it.
• Main results:
  • Before surgery, among the 80 patients: 41 (51.3%) had decreased NK counts (below 155 cells per microliter), 36 (45.0%) normal and 3 (3.7%) increased. The median was 137 cells per microliter.
  • Preoperative thrombosis differed among the three preoperative NK groups (P = 0.023). Only 3 of the 80 patients had preoperative thrombosis: per Table 2, 1 of 41 in the decreased group, 1 of 36 in the normal group and 1 of 3 in the increased group.
  • Plasma transfusion volume (P = 0.004) and length of hospital stay (P = 0.023) differed among the preoperative NK groups. In multivariate analysis, plasma transfusion above 600 mL versus 600 mL or less had OR 0.242 (95% CI 0.079 to 0.741), P = 0.013.
  • Preoperative thrombosis affected 3 of 80 patients (3.7%).
  • The authors reported that median NK counts rose from 137 to 278 cells per microliter. The 137 figure is from the 80-patient preoperative group and 278 from the 64-patient postoperative group. NK counts increased after surgery in 60.9% of the 64 postoperative patients (39 of 64 in Table 2).
  • In the 64 postoperative patients, KPS score was associated with postoperative NK change group (P = 0.048). In multivariate analysis, KPS of 90 or more versus below 90 had OR 0.166 (95% CI 0.028 to 0.987), P = 0.048.
  • After surgery, NK change groups differed in IL-4 (P = 0.020), IL-5 (P = 0.007), IL-6 (P = 0.016) and IL-8 (P = 0.018). No surgery-related parameter was associated with postoperative NK change.
  • Of the 80 patients, 9 (11.3%) had died by February 28, 2025, and median overall survival was not reached. Overall survival did not differ significantly among the preoperative NK groups (P = 0.533).
  • Of the 64 postoperative patients, 3 (4.7%) had died. Postoperative NK change showed no clear association with overall survival (P = 0.472, HR = 7.728).
  • In the 80-patient Cox analysis, the authors named high PSS (P = 0.015), lymph node metastasis (HR 8.266, 95% CI 1.504 to 45.432, P = 0.015), substantial intraoperative blood loss (P = 0.013) and low preoperative CD8+ T cells (P = 0.001) as poor prognostic factors.
  • In the 64 postoperative patients, postoperative IL-17 was independently correlated with prognosis: above 28.25 pg/mL versus 28.25 or less had HR 0.029 (95% CI 0.002 to 0.470), P = 0.013.
  • A weighted regression model of NK change used 120 data points from 64 patients and had an adjusted R-squared of 0.810. Its predictors (all P less than 0.001) were postoperative NK (beta 0.386), preoperative NK (beta -0.391), centered PCI (beta -1.143), postoperative CD8+ T cells (beta 0.050) and follow-up time (beta 8.068 per month).
• The authors' conclusion: The authors concluded that the study described the dynamic changes in blood NK cells in MPM patients and their clinical significance, that CRS + HIPEC enhanced NK cell function through remodeling of the immune microenvironment, and that they established a model predicting postoperative NK recovery. In their discussion they also wrote that there is no direct evidence of a mechanistic link between CRS + HIPEC and NK recovery in MPM.
• Limitations the authors state:
  • Single-center retrospective design with a limited sample size (64 patients in the longitudinal analysis)
  • NK cell functions such as degranulation capacity, and other immune components such as the Treg/MDSC ratio, were not measured
  • The multivariate analyses were exploratory and may give false-positive results because there was no correction for multiple comparisons
  • Confounding factors, such as postoperative complications or persistent inflammation, could not be excluded as explanations for the postoperative NK increase

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: HIPEC, Peritoneal Mesothelioma, Cytoreductive Surgery, Prognosis, Multivariate Analysis, Metastasis, Overall Survival, Peritoneal Cancer Index (PCI).

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• Repeated cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with recurrent peritoneal carcinomatosis — N. Vassos, T. Förtsch, et al. (2016)
• Underutilization of CRS, HIPEC & PIPAC in peritoneal mesothelioma across a German nationwide cohort — V. Müller, M. Hornung, et al. (2026)
• Prognostic importance of the neutrophil-to-lymphocyte ratio in malignant peritoneal mesothelioma patients receiving cytoreductive surgery and hyperthermic intraperitoneal chemotherapy — Z. Xinjing, G. Lei, et al. (2025)
• Analysis of Treatment Strategies and Outcomes in Malignant Peritoneal Mesothelioma: Insights From a Multi-Center Study — S. Yaşar, F. Yılmaz, et al. (2024)

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