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Immune Checkpoint Inhibitor–Induced Cellular Injury in Advanced Melanoma: A Prospective Clinical Study of Oxidative Stress, Immune Activation, and Therapeutic Outcomes

Thabo M. Nkosi, MD, 1*, Naledi P. Mokoena, PhD 2 Siphesihle Dlamini, MD 3 ORCID 

1Department of Medical Oncology, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa. 2Division of Clinical Oncology, University of the Witwatersrand and Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa. 3Department of Immunology and Cancer Research, University of KwaZulu-Natal and Inkosi Albert Luthuli Central Hospital, Durban, South Africa.

DOI: 10.18081/2378-5225/12.21  
Cited by 0

 Article history: Received 04 December 2022 · Revised 03 January 2023 · Accepted 02 February 2023 · Published 19 February 2023

© 2023 Nkosi, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0). 

CC BY 4.0                                                                                                   

Abstract

Background: Immune checkpoint inhibitors have significantly improved survival outcomes in advanced melanoma; however, immune-mediated cellular injury and inflammatory toxicities remain major clinical challenges. The present study investigated oxidative stress, inflammatory cytokine activation, histopathological alterations, and immune-mediated tissue injury in melanoma patients receiving checkpoint inhibitor therapy in South Africa.

Objective: To evaluate the relationship between immune checkpoint inhibitor therapy, oxidative stress biomarkers, inflammatory cytokines, histopathological changes, and clinical outcomes in melanoma patients undergoing immunotherapy.

Methods: This prospective clinical study included 120 patients with histologically confirmed stage III or IV melanoma treated with nivolumab, pembrolizumab, or combined nivolumab plus ipilimumab therapy at tertiary oncology centers in South Africa between January 2024 and December 2025. Clinical assessment, radiological response evaluation, serum oxidative stress markers, inflammatory cytokine profiling, histopathological examination, and immunohistochemical analyses were performed before and during therapy. Oxidative stress parameters included malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione peroxidase (GPx). Cytokine analysis included TNF-α, IL-6, and IFN-γ measurements. Progression-free survival and immune-related adverse events were evaluated.

Results: A total of 112 patients completed the study and were included in the final analysis. Objective clinical responses were observed in 56.3% of patients, with higher response rates in the combination therapy group. Significant increases in oxidative stress markers were observed following treatment initiation, including elevated MDA and ROS levels (p<0.001), while antioxidant enzyme activities significantly decreased. Serum TNF-α, IL-6, and IFN-γ concentrations increased markedly during therapy, reflecting enhanced systemic immune activation. Histopathological analysis demonstrated increased tumor necrosis, apoptotic activity, and dense CD8+ lymphocytic infiltration in responding tumors. Patients with high intratumoral CD8+ T-cell infiltration exhibited significantly prolonged progression-free survival compared with patients showing low immune infiltration (p=0.002). Immune-related adverse events occurred in 63.4% of patients, with elevated IL-6 and ROS levels significantly associated with severe inflammatory toxicity.

Conclusion: Checkpoint inhibitor therapy in melanoma patients induces substantial immune-mediated cellular injury characterized by oxidative stress, inflammatory cytokine activation, and enhanced cytotoxic immune infiltration. While these mechanisms contribute to effective tumor destruction and improved survival outcomes, excessive inflammatory activation may also result in clinically significant immune-related toxicity. The findings provide important prospective clinical evidence regarding the biological mechanisms of immunotherapy-associated cellular injury in melanoma patients from South Africa and support the potential value of oxidative stress and cytokine biomarkers in predicting therapeutic response and treatment-related complications.

Keywords: Melanoma; Immune checkpoint inhibitors; Oxidative stress; Cellular injury; Cytokines; Immunotherapy; PD-1; CTLA-4.

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BM-Publisher · Pathophysiology of Cell Injury Journal (PCIJ) · E-ISSN 2378-5225 · DOI Prefix 10.18081/pcij/2378-5225

Pathophysiology of Cell Injury Journal (PCIJ)
E-ISSN 2378-5225 · Biannual
BM-Publisher (London, UK)
Open Access

Vol 12, Issue 1 (February 2023), pp. 21–43

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Nkosi TM, Mokoena, Dlamini S. Immune Checkpoint Inhibitor–Induced Cellular Injury in Advanced Melanoma: A Prospective Clinical Study of Oxidative Stress, Immune Activation, and Therapeutic Outcomes. Pathophysiology of Cell Injury Journal (PCIJ). 2023;12(1):21–43. doi: 10.18081/2378-5225/12.21.

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