Magnesium Is Associated with Favorable Outcomes of Cancer Patients Treated with Immune Checkpoint Inhibitors

Background: In recent years, tumor immunotherapy has rapidly evolved, profoundly altering the landscape of cancer treatment^[1]. Despite these notable achievements, the overall efficacy of immune checkpoint inhibitors (ICIs) remains somewhat constrained^[2,3], necessitating the identification of factors influencing treatment outcomes to enhance response rates. Magnesium ions serve as second messengers within immune cells^[4], regulating intracellular signaling pathways that impact NK cell and CD8⁺ T cell activation and cytotoxicity^[5]. This study aims to investigate the relationship between serum magnesium levels and therapeutic response as well as prognosis in patients undergoing ICIs therapy.

Methods: A retrospective study was conducted spanning from August 2012 to May 2023, encompassing 1441 patients from two centers: Tianjin Medical University Cancer Institute and Hospital (TMUCIH) and Shandong Cancer Hospital and Institute (SCHI). The cohort consisted of patients newly diagnosed with three prevalent cancer types-lung cancer, esophageal cancer, and Hodgkin's lymphoma-all meeting WHO classification standards for tumors. Included in the study were patients who received various ICIs treatments, such as IBI318, pembrolizumab, nivolumab, atezolizumab, durvalumab, cemiplimab, tislelizumab, toripalimab, and sintilimab, with monitoring of their serum magnesium ion levels. Institutional review board approval was secured for this investigation.

Results: The study included patients diagnosed with three prevalent types of cancer: 1042 with lung cancer, 270 with esophageal cancer, and 129 with Hodgkin's lymphoma, all of whom underwent treatment with ICIs accompanied by serum magnesium level assessments . Based on the normal serum magnesium ion range (0.7-1.0 mmol/L), magnesium levels were classified into low, normal, and high categories. In lung cancer, the distribution among these categories was 9.21%, 83.78%, and 7.00%, respectively. For esophageal cancer, the corresponding percentages were 4.07%, 93.33%, and 2.59%, and for Hodgkin's lymphoma, they were 3.1%, 91.47%, and 5.43%. Patients receiving ICIs therapy were categorized based on their clinical responses, with higher serum magnesium levels observed correlating with higher objective response rates (ORR). To further explore the relationship between magnesium levels and outcomes in ICI therapy, prognostic data and magnesium concentration information for all patients were integrated. Using the 'surv_cutpoint()' function in R, an optimal magnesium ion cutoff value of 0.79mmol/L was identified. Based on this cutoff, patients were stratified into low and high magnesium groups across the three cohorts. Additionally, we analyzed PFS and OS between these two groups. Kaplan-Meier plots demonstrated significantly longer PFS and OS in the high group . Subsequently, based on patients' baseline characteristics and treatment regimens (including the lines of ICIs therapy and whether receiving combination therapy), we conducted univariate and multivariate analyses of patient PFS and OS using hazard ratio [HR]. Multivariate Cox regression analysis indicated that Mg²⁺ levels >=0.79 mmol/L was beneficial for prolonging PFS and OS. These findings underscore the predictive value of serum magnesium levels in evaluating clinical outcomes among patients receiving ICIs therapy.

Conclusion: This multicenter study demonstrates that patients receiving ICIs exhibit significantly improved outcomes among those with elevated serum magnesium levels compared to those with low levels. Further prospective validation studies are essential to evaluate magnesium levels in ICI-treated patients and to supplement magnesium preparations in patients with magnesium deficiency to confirm these findings.

No relevant conflicts of interest to declare.