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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively triggers apoptosis in malignant, infected, or stressed cells while sparing normal tissues, making it an attractive therapeutic candidate. However, many tumors exhibit intrinsic or acquired resistance to TRAIL, driven by reduced DR4\/DR5 surface expression, elevated decoy receptor levels, dysregulated DISC assembly, overexpression of c-FLIP and anti-apoptotic Bcl-2 family proteins, or activation of survival pathways such as NF-\u03baB, PI3K\/Akt, and MAPK. Moreover, TRAIL receptors can initiate non-canonical signaling pathways that promote migration, invasion, and metastasis in specific oncogenic contexts, thereby further limiting therapeutic efficacy. We aimed to integrate mechanistic insights into TRAIL biology with current therapeutic advances, providing a comprehensive framework for understanding resistance and for designing rational TRAIL-based combination strategies. We summarized the structural and signaling features of TRAIL receptors, outlined the major determinants of TRAIL sensitivity, and evaluated predictive biomarkers that may guide patient selection. In addition, we examined next-generation TRAIL agonists and targeted delivery systems developed to enhance receptor clustering, pharmacokinetics, and tumor specificity. Together, these insights highlight the therapeutic promise of mechanistically informed TRAIL combinations. A deeper understanding of resistance pathways and biomarker-guided stratification will be essential for restoring apoptotic competence and improving clinical outcomes.<\/jats:p>","DOI":"10.3390\/ijms27167068","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T08:01:36Z","timestamp":1786089696000},"page":"7068","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Helping Apo2L\/TRAIL in the Battle: Synergistic Therapeutic Approaches for Cancer Therapies"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9166-8417","authenticated-orcid":false,"given":"Elena Valeria","family":"Fuior","sequence":"first","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalina","family":"Dumitrescu","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1656-0400","authenticated-orcid":false,"given":"Marius Gabriel","family":"Multescu","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca Sanziana","family":"Daraban","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9686-7606","authenticated-orcid":false,"given":"Madalin","family":"Ghinea","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oana","family":"Mirancea","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2651-3608","authenticated-orcid":false,"given":"George E. D.","family":"Petrescu","sequence":"additional","affiliation":[{"name":"Neurosurgery Clinic, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Department of Neurosurgery, Bagdasar-Arseni Emergency Clinical Hospital, 041915 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix Mircea","family":"Brehar","sequence":"additional","affiliation":[{"name":"Neurosurgery Clinic, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Department of Neurosurgery, Bagdasar-Arseni Emergency Clinical Hospital, 041915 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7976-8992","authenticated-orcid":false,"given":"Ana Maria","family":"Vacaru","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6944-7255","authenticated-orcid":false,"given":"Radu","family":"Ionita","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Violeta Georgeta","family":"Bivol","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina Florina","family":"Tudorache","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea","family":"Popa","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3898-0940","authenticated-orcid":false,"given":"Ioana Madalina","family":"Fenyo","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8387-6830","authenticated-orcid":false,"given":"Evangelia","family":"Zvintzou","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"},{"name":"Pharmacology Laboratory, Department of Medicine, University of Patras, 26504 Rio Achaias, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1290-1346","authenticated-orcid":false,"given":"Anca Violeta","family":"Gafencu","sequence":"additional","affiliation":[{"name":"Institute of Cellular Biology and Pathology \u201cNicolae Simionescu\u201d, Romanian Academy, 050568 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/1074-7613(95)90057-8","article-title":"Identification and characterization of a new member of the TNF family that induces apoptosis","volume":"3","author":"Wiley","year":"1995","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12687","DOI":"10.1074\/jbc.271.22.12687","article-title":"Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family","volume":"271","author":"Pitti","year":"1996","journal-title":"J. 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