{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:03:27Z","timestamp":1790053407277,"version":"4.0.1"},"reference-count":50,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01AI176537"],"award-info":[{"award-number":["R01AI176537"]}]},{"name":"National Institutes of Health","award":["R01HL180677"],"award-info":[{"award-number":["R01HL180677"]}]},{"name":"National Institutes of Health","award":["R21AI191628"],"award-info":[{"award-number":["R21AI191628"]}]},{"award":["R01AI176537"],"award-info":[{"award-number":["R01AI176537"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01HL180677"],"award-info":[{"award-number":["R01HL180677"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21AI191628"],"award-info":[{"award-number":["R21AI191628"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Anticancer peptides (ACPs) are frequently discussed as a single therapeutic class, yet the term encompasses molecules that perform markedly different jobs: direct tumor-cell killing, intracellular target modulation, tumor homing and penetration, or selective delivery of a separate payload. This functional diversity creates opportunity, but it also obscures why many potent peptides fail during translation. In this review, we organize ACPs according to their intended pharmacologic role and examine the molecular and product-development principles that determine whether an active sequence can become a useful medicine. Charge, amphipathicity, conformation, target affinity, cellular entry, protease resistance, tissue exposure, and manufacturability must be optimized as an integrated profile rather than as independent attributes. Representative clinical programs\u2014including the oncolytic peptide LTX-315, the cell-penetrating peptide p28, the stapled peptide ALRN-6924, the tumor-penetrating peptide CEND-1, and the cyclic integrin inhibitor cilengitide\u2014illustrate both the reach of peptide pharmacology and recurrent causes of attrition. We propose a developability-centered workflow that links mechanism, route of administration, pharmacokinetics, pharmacodynamics, biomarker strategy, formulation and chemistry, manufacturing, and controls from the beginning of discovery. For the next generation of ACP development, the most credible opportunities lie in route-matched local or regional therapy, mechanism-based combinations, experimentally constrained artificial intelligence, and peptide-enabled delivery systems supported by fit-for-purpose translational models.<\/jats:p>","DOI":"10.3390\/molecules31183319","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:12:09Z","timestamp":1789999929000},"page":"3319","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anticancer Peptides: Design Principles, Translational Bottlenecks, and Emerging Opportunities"],"prefix":"10.3390","volume":"31","author":[{"given":"Marissa E.","family":"Di","sequence":"first","affiliation":[{"name":"Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2028-2087","authenticated-orcid":false,"given":"Yuanpu Peter","family":"Di","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Center for Translational Science, Herbert Wertheim College of Medicine, Florida International University, Port St. Lucie, FL 34987, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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