{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T20:18:17Z","timestamp":1790367497623,"version":"4.1.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"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. Oncol."],"abstract":"<jats:p>Programmed death-1 (PD-1)\/programmed death ligand-1 (PD-L1) inhibitors and cytotoxic Lymphocyte-associated protein 4 (CTLA-4) inhibitors are the core classes of immune checkpoint inhibitors (ICIs) widely used in cancer treatment. These agents, including PD-1, PD-L1, and CTLA4 inhibitors, have demonstrated efficacy across multiple cancer types, enhancing progression free survival (PFS) and overall survival (OS). However, their use is associated with immune related adverse events (irAEs) that can manifest as skin rashes, hepatitis, diarrhea, colitis, hypopituitarism, and pneumonitis, among other conditions. In this systematic review, we discuss the safety and efficacy of ICIs based on 15 randomized controlled trials and cohort studies that met our eligibility criteria. All selected studies focused on analysing primary clinical outcomes including OS, PFS, objective response rate (ORR), and irAEs. These findings demonstrate that ICIs offer durable antitumor activity with favourable outcomes observed in patients with high tumour mutational burden (TMB) and PD-L1 expression. However, toxicity remains a significant concern, as some reports show substantial adverse events requiring immunosuppressive management. While PD-L1 expression and TMB are established biomarkers for predicting ICI response, their role in predicting immune-related adverse events remains investigational and is not supported by robust evidence. This review further examines combination strategies, including dual checkpoint blockade and ICI combined with chemotherapy, which have demonstrated superior clinical outcomes compared with monotherapy but are associated with increased toxicity. Future research should focus on refining patient selection criteria, optimizing toxicity management protocols, and identifying novel predictive biomarkers for ICI therapy. Understanding these aspects will facilitate the development of more effective ICI-based treatments with improved benefit-to-risk ratios, ultimately enhancing patient outcomes in oncology.<\/jats:p>","DOI":"10.3389\/fonc.2026.1789760","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T04:48:26Z","timestamp":1779252506000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Immune Checkpoint Inhibitors: efficacy, safety, and biomarkers - a systematic review"],"prefix":"10.3389","volume":"16","author":[{"given":"Hebatalla","family":"Ismail","sequence":"first","affiliation":[{"name":"Medical Oncology, St. Vincent\u2019s University Hospital, UCD Cancer Centre","place":["Dublin, Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anees","family":"Hassan","sequence":"additional","affiliation":[{"name":"Medical Oncology, University Hospital Limerick","place":["Limerick, 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