Cisplatin-induced peripheral neuropathy (CIPN) is a frequent and often persistent complication in survivors of testicular germ cell tumors (GCT) treated with curative therapy. Although several mechanisms have been proposed, the biological drivers of long-term neurotoxicity remain incompletely understood. Disruption of intestinal barrier integrity during chemotherapy or radiotherapy may promote gut microbial translocation (GMT), leading to systemic immune activation and chronic inflammation that could contribute to neuropathy development. This study investigated the relationship between circulating biomarkers of GMT and symptoms of CIPN in long-term GCT survivors.
A total of 170 GCT survivors (median age 41 years) from the National Cancer Institute of Slovakia were included, with a median follow-up of 10 years after treatment. Participants completed the EORTC QLQ-CIPN20 questionnaire assessing sensory, motor, and autonomic neuropathy. Peripheral blood samples were analyzed for plasma biomarkers associated with gut microbial translocation and innate immune activation, including soluble CD14 (sCD14), high-mobility group box-1 (HMGB1), lipopolysaccharide (LPS), and D-lactate. Associations between biomarker concentrations and CIPN scores were evaluated across treatment groups: orchiectomy only (active surveillance, n=28), cisplatin-based chemotherapy (n=119), radiotherapy (n=14), and combined chemoradiotherapy (n=9).
Patients with higher plasma sCD14 levels had significantly higher overall CIPN scores (7.6% increase, p=0.019) and worse sensory function (9.5% increase, p=0.019) compared with those with lower levels. Patients treated with chemotherapy exhibited significantly higher plasma sCD14 levels than those under active surveillance (6613 vs. 3768 μg/L, p = 0.009). Among chemotherapy-treated patients, elevated sCD14 was associated with a higher risk of motor neuropathy (RR = 3.5, 95% CI 1.21-10.14, p=0.020). In survivors receiving combined chemotherapy and radiotherapy, increased sCD14 levels were associated with a higher risk of autonomic neuropathy (RR = 2.85, 95% CI 1.11-7.30, p=0.029). Elevated HMGB1 was also associated with an increased probability of autonomic dysfunction (RR = 2.15, 95% CI 1.07-4.33, p=0.015). No significant associations were observed between cumulative cisplatin dose and GMT biomarkers.
Elevated biomarkers of gut microbial translocation, particularly sCD14, are associated with increased severity of CIPN in long-term GCT survivors. These findings support the hypothesis that treatment-related intestinal barrier disruption and subsequent immune activation may contribute to persistent neurotoxicity in cancer survivorship.
Frontiers in immunology. 2026 May 11*** epublish ***
Dominika Rychtarikova, Katarina Kalavska, Jana Obertova, Patrik Palacka, Katarina Rejlekova, Zuzana Sycova-Mila, Zuzana Orszaghova, Peter Lesko, Rateb Alzeer, Lucia Vasilkova, Daniela Svetlovska, Beata Mladosievicova, Michal Pastorek, Matej Rychtarik, Barbora Vlkova, Peter Celec, Michal Mego, Michal Chovanec
2nd Department of Oncology, Comenius University, Faculty of Medicine &, National Cancer Institute, Bratislava, Slovakia., Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia., Department of Psychology, Faculty of Philosophy, Comenius University, Bratislava, Slovakia., Department of Clinical Trials, National Cancer Institute, Bratislava, Slovakia., Institute of Pathological Physiology, Comenius University, Faculty of Medicine, Bratislava, Slovakia., Faculty of Medicine, Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia.