{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:46:18Z","timestamp":1791413178461,"version":"4.3.3"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"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>Checkpoint inhibitors targeting the PD-1\/PD-L1 axis have revolutionized cancer immunotherapy, yet response rates remain limited. To enhance efficacy, next-generation approaches target T cell-activating cytokines to PD-1 via antibodies. The goal is simultaneous checkpoint blockade and cytokine potentiation but fine-tuning cytokine activity such that checkpoint inhibition can be preserved with manageable toxicity has been a difficult challenge. We hypothesized that targeting a highly attenuated interleukin (IL)-18 to PD-1 can activate PD-1+ T cells and oppose exhaustion while antagonizing PD-1. We generated a highly attenuated IL-18 variant, which is resistant to IL-18BP binding and assessed its receptor binding ability. Tumor growth inhibition was evaluated across multiple models. Additionally, we examined post-remission tumor resistance and lymphocyte infiltration into the tumor ex vivo using flow cytometry. The IL-18 fusion resisted interleukin-18 binding protein (IL-18BP) inhibition and exhibited a 10,000-fold reduction in activity while preserving cis-signaling and demonstrated strong efficacy across tumor models. It increased CD8+ progenitor-exhausted tumor-infiltrating lymphocytes (TILs) while reducing myeloid TILs. Attaching a highly attenuated IL-18 to an anti-PD-1 antibody goes beyond simply targeting a cytokine to PD-1, representing a novel cytokine-enhanced checkpoint inhibitor that activates PD-1+ T cells via the cytokine receptor while simultaneously antagonizing PD-1.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1718321","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T06:45:03Z","timestamp":1766040303000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting highly attenuated IL-18 to PD-1 for enhanced anti-tumor activity"],"prefix":"10.3389","volume":"16","author":[{"given":"Xueyuan","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix 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