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These properties have made them as efficient drug-delivery tools to deliver therapeutic molecules to cells and tissues in a nontoxic manner, including small molecules, DNA, siRNA, therapeutic proteins and other various nanoparticles. However, the poor serum stability and low tumor targeting ability also hindered their broad application. Besides, inappropriate chemical modification can lead to membrane disruption and nonspecific toxicity. In this paper, we first reviewed recent advances in the CPP applications for cancer therapy via covalent or non-covalent manners. We carefully analyzed the advantages and disadvantages of each CPP modifications for drug delivery. Then, we concluded the recent progress of their clinical trials for different diseases. Finally, we discussed the challenges and opportunities CPPs met to translate into clinical applications. This review presented a new insight into CPPs for drug delivery, which could provide advice on the design of clinically effective systemic delivery systems using CPPs.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1540192","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T02:15:59Z","timestamp":1737512159000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":44,"title":["Applications of cell penetrating peptide-based drug delivery system in immunotherapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Jing-Jing","family":"Du","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru-Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangchi","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongheng","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Xiang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"XianShi","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2022.03.010","article-title":"Unleashing cell-penetrating peptide applications for immunotherapy","volume":"28","author":"Koo","year":"2022","journal-title":"Trends Mol Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3339","DOI":"10.3390\/molecules29143339","article-title":"Cell-penetrating peptide-mediated biomolecule transportation in artificial lipid vesicles and living cells","volume":"29","author":"Miwa","year":"2024","journal-title":"Molecules"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(88)90262-0","article-title":"1988 Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein","volume":"55","author":"Green","year":"1988","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90417-0","article-title":"Mutational analysis of HIV-1 Tat minimal domain peptides: Identification of trans-dominant mutants that suppress HIV-LTR-driven gene expression","volume":"58","author":"Green","year":"1989","journal-title":"Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.25.16010","article-title":"A truncated HIV-1 tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus","volume":"272","author":"Viv\u00e8s","year":"1997","journal-title":"J Biol Chem"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.30.18188","article-title":"Cell internalization of the third helix of the antennapedia homeodomain is receptor-independent","volume":"271","author":"Derossi","year":"1996","journal-title":"J Biol Chem"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1080\/17425247.2019.1676720","article-title":"Cell penetrating peptides: the potent multi-cargo intracellular carriers. 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