{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T04:45:51Z","timestamp":1785732351920,"version":"3.56.0"},"reference-count":256,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["R01CA225958"],"award-info":[{"award-number":["R01CA225958"]}]},{"name":"National Cancer Institute","award":["R01CA291771"],"award-info":[{"award-number":["R01CA291771"]}]},{"award":["R01CA225958"],"award-info":[{"award-number":["R01CA225958"]}],"id":[{"id":"https:\/\/ror.org\/02t771148","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01CA291771"],"award-info":[{"award-number":["R01CA291771"]}],"id":[{"id":"https:\/\/ror.org\/02t771148","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/045p44t13","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["T32GM144303"],"award-info":[{"award-number":["T32GM144303"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"award":["T32GM144303"],"award-info":[{"award-number":["T32GM144303"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Cancer immunotherapy via targeting immune checkpoint proteins (ICPs) has transformed the treatment of multiple malignancies, offering improved clinical outcomes over conventional therapies. Immune checkpoint inhibitors (ICIs), including FDA-approved monoclonal antibodies against CTLA-4, PD-1, and PD-L1, as well as emerging agents targeting novel ICPs, have demonstrated strong therapeutic efficacy by restoring antitumor immune responses. In parallel, RNA interference (RNAi)-based approaches involving microRNAs (miRNAs) and small interfering RNAs (siRNAs) have emerged as promising alternative strategies for modulating ICP expression at the posttranscriptional level, enabling selective and simultaneous regulation of multiple immune checkpoint pathways. Preclinical and early clinical studies have indicated effective downregulation of target ICP expression and enhanced antitumor immunity across diverse cancer models. Due to the inherent instability of RNA molecules, the development of RNAi therapeutics has been accompanied by advances in delivery platforms. In this review, we discuss the biological functions of established and novel ICPs, along with immunotherapeutics approved by the FDA and under Phase III clinical development. We also provide an overview of the RNAi mechanism of miRNAs and siRNAs, highlight endogenous miRNAs that regulate immune checkpoint pathways, and summarize ICP-targeting RNAi agents and their corresponding delivery systems under preclinical and clinical development. Collectively, these advances underscore the potential of RNAi-based immune checkpoint modulation, complementing existing ICIs and expanding the next generation of cancer immunotherapy.<\/jats:p>","DOI":"10.3390\/ph19081212","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T01:43:27Z","timestamp":1785721407000},"page":"1212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Immune Checkpoint Proteins in Cancer Therapy and the Potential of RNAi-Based Immunotherapy"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2069-5665","authenticated-orcid":false,"given":"Katherine Kaixin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1441-4012","authenticated-orcid":false,"given":"Ai-Ming","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/s41571-023-00794-7","article-title":"Immune-checkpoint inhibition for resectable non-small-cell lung cancer\u2014Opportunities and challenges","volume":"20","author":"Mountzios","year":"2023","journal-title":"Nat. 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