PERSPECTIVE article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1629879
This article is part of the Research TopicCurrent Insights in Melanoma Immunology, Immune Escape and Immunotherapy AdvancesView all 9 articles
CTLA-4 and PD-1 Combined Blockade Therapy for Malignant Melanoma Brain Metastases: Mechanisms, Challenges, and Prospects
Provisionally accepted
- Department of Orthopedics, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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Malignant melanoma brain metastases (MBM) represent one of the deadliest complications of melanoma, with an incidence rate of 7.3%. Among patients with acral and mucosal melanoma, the cumulative 5-year incidence can reach 19.5%, accompanied by poor prognosis. The bloodbrain barrier (BBB), an immunosuppressive central nervous system (CNS) microenvironment, and tumor immune evasion collectively limit the efficacy of traditional therapies. Cytotoxic Tlymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), as critical immune checkpoints, play pivotal roles in the progression of MBM. This study systematically analyzes the synergistic mechanisms, clinical outcomes, and challenges of CTLA-4 and PD-1 combined blockade therapy in MBM. The findings indicate that this combination therapy leverages a "priming and boosting" biological mechanism: CTLA-4 blockade broadens Tcell responses during the initial activation phase, while PD-1 blockade sustains T-cell activity during the effector phase, significantly improving intracranial response rates (46%, compared to 20% for monotherapy). Furthermore, the combination therapy increases the CD8+/Treg ratio and promotes memory CD8+ T-cell formation, enabling durable antitumor immune surveillance. However, challenges such as a 54% incidence rate of grade 3-4 adverse events and suboptimal therapeutic regimens remain. To address these issues, this study proposes a multi-tiered adverse event management system, personalized risk assessment models, and treatment optimization strategies based on real-time monitoring and dynamic adjustments. Future directions include developing precision stratified therapies based on immunogenomics, exploring multi-target synergistic approaches, and implementing intelligent adverse event prediction and management systems to maximize therapeutic efficacy and minimize toxicity, providing more effective treatment for MBM patients.
Keywords: Melanoma brain metastases, CTLA-4, PD-1, combined blockade therapy, immune checkpoint inhibitors, Adverse event management, precision therapy
Received: 16 May 2025; Accepted: 13 Jun 2025.
Copyright: © 2025 Wang, Feng and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ying-Fa Feng, Department of Orthopedics, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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