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This structured, registry-derived narrative review, supported by expert-guided interpretation, was designed to identify the most clinically meaningful development directions among strategies intended to overcome the limitations of PD-1\/PD-L1 inhibitor therapy and most likely to generate practice-relevant late-phase readouts through 2030. We searched major international and regional clinical trial registries and applied harmonization, cross-registry deduplication, formal late-phase filtering, semi-automated prioritization, and manual documentation-based verification. The final analytic corpus was interpreted using a two-level framework: first, by the dominant clinicobiological barrier limiting PD-1\/PD-L1 efficacy, and second, by three criteria of clinical promise - exposure and effect, manageable toxicity, and confirmable clinical benefit. This approach narrowed a registry-derived pool of more than 13, 000 PD-1\/PD-L1 studies to 47 clinically relevant late-phase programs that define the most likely near-term development trajectory through 2030. Within this corpus, a narrower confirmatory subset emerged in which incremental clinical benefit is tested most directly in comparative designs. These programs represent the most plausible leading strategies of the next phase of PD-1\/PD-L1-based clinical development and provide a clinically interpretable framework for prioritizing future translational and late-phase efforts.<\/jats:p>","DOI":"10.3389\/fonc.2026.1875861","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T04:20:20Z","timestamp":1784521220000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Late-phase strategies to overcome limitations of PD-1\/PD-L1 therapy: a clinical development trajectory through 2030"],"prefix":"10.3389","volume":"16","author":[{"given":"Elena A.","family":"Andresyuk","sequence":"first","affiliation":[{"name":"The Laboratory of Bio- and Chemoinformatics, School of Computer Science, Physics and Technology, HSE University","place":["St. Petersburg, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalya O.","family":"Porozova","sequence":"additional","affiliation":[{"name":"The Laboratory of Bio- and Chemoinformatics, School of Computer Science, Physics and Technology, HSE University","place":["St. Petersburg, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgii D.","family":"Londaridze","sequence":"additional","affiliation":[{"name":"Department of AI, Medsi Clinic","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan S.","family":"Moiseev","sequence":"additional","affiliation":[{"name":"Raisa Maximovna (RM) Gorbacheva Research Institute, Pavlov Medical University","place":["St. Petersburg, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polina V.","family":"Kotselyabina","sequence":"additional","affiliation":[{"name":"Raisa Maximovna (RM) Gorbacheva Research Institute, Pavlov Medical University","place":["St. Petersburg, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri B.","family":"Porozov","sequence":"additional","affiliation":[{"name":"The Laboratory of Bio- and Chemoinformatics, School of Computer Science, Physics and Technology, HSE University","place":["St. Petersburg, Russia"]},{"name":"Advitam Laboratory","place":["Belgrade, Serbia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1038\/s41392-023-01522-4","article-title":"Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends","volume":"8","author":"Sun","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.017","article-title":"Primary, adaptive, and acquired resistance to cancer immunotherapy","volume":"168","author":"Sharma","year":"2017","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/s41577-023-00973-8","article-title":"Immunotherapy combination approaches: mechanisms, biomarkers and clinical observations","volume":"24","author":"Butterfield","year":"2024","journal-title":"Nat Rev Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-025-09105-7","article-title":"PD-1\/PD-L1 cancer immunotherapeutics reshape tumor microenvironment - 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