{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:26:22Z","timestamp":1792178782277,"version":"4.4.0"},"reference-count":79,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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 blood-brain barrier (BBB), an immunosuppressive central nervous system (CNS) microenvironment, and tumor immune evasion collectively limit the efficacy of traditional therapies. Cytotoxic T-lymphocyte-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 \u201cpriming and boosting\u201d biological mechanism: CTLA-4 blockade broadens T-cell 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\u20134 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.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1629879","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T05:29:29Z","timestamp":1751347769000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["CTLA-4 and PD-1 combined blockade therapy for malignant melanoma brain metastases: mechanisms, challenges, and prospects"],"prefix":"10.3389","volume":"16","author":[{"given":"Jia-Wen","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Fa","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Hui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"viii144","DOI":"10.1093\/neuonc\/noae165.0565","article-title":"Epid-29. 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