{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T17:00:54Z","timestamp":1789146054849,"version":"build-2803163510"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The recent U.S. FDA approval of lifileucel, a non-engineered, autologous tumor-infiltrating lymphocyte (TIL) therapy, for unresectable or metastatic melanoma represents a major milestone for cellular therapies in solid tumors. This review examines the clinical foundation, regulatory development, limitations, and evolution of TIL therapy in metastatic melanoma. Randomized academic data from the phase III M14TIL trial established the efficacy of TIL therapy. The C-144\u201301 study leading to lifileucel approval demonstrated median duration of response of 36.5 months, median overall survival (OS) of 13.9 months, and estimated 5-year OS rate of 19.7%, a major advance in this anti\u2013PD-1\/PD-L1 resistant cohort without effective treatment options. Despite durable responses, classical TIL therapy requires intensive nonmyeloablative lymphodepletion and high-dose interleukin-2 (IL-2), contributing to substantial toxicity and treatment-related mortality that remain barriers to broader implementation. We discuss safety-driven trial terminations related to cytokine augmentation and feasibility or strategic factors underlying discontinuation of programs, underscoring translational challenges beyond biologic efficacy. Engineered TIL platforms aim to improve persistence and reduce systemic cytokine dependence. OBX-115, designed with regulatable membrane-bound IL-15 expression, eliminates the need for IL-2 infusion and has shown early clinical activity. KSQ-001EX uses CRISPR\/Cas9 to inactivate SOCS1, while KSQ-004EX additionally targets Regnase-1 to enhance TIL function. Emerging strategies including IL-2\u2013independent expansion platforms, PD-1\u2013edited TILs, and neoantigen-enriched products illustrate ongoing innovation. TIL therapy remains among the most promising strategies in melanoma and solid tumors after immunotherapy failure. Ongoing research aims to optimize cell dose, phenotype, tumor procurement, treatment sequencing, and rational combinations to improve durable benefit.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1801722","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T06:55:39Z","timestamp":1774421739000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Evolving therapeutic pipeline for tumor-infiltrating lymphocytes in metastatic melanoma \u2013 a review"],"prefix":"10.3389","volume":"17","author":[{"given":"James Fan","family":"Wu","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, Medical College of Wisconsin","place":["Milwaukee, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Abbas","family":"Abid","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Aga Khan University","place":["Karachi, Pakistan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharda P.","family":"Singh","sequence":"additional","affiliation":[{"name":"Texas Tech University Health Science Center, UMC Cancer Center","place":["Lubbock, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Mohlere","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology, The University of Texas Health Science Center at","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Bilal","family":"Abid","sequence":"additional","affiliation":[{"name":"Texas Tech University Health Science Center, UMC Cancer Center","place":["Lubbock, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2210233","article-title":"Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma","volume":"387","author":"Rohaan","year":"2022","journal-title":"New Engl J Med"},{"key":"B2","unstructured":"FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.00612","article-title":"Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma","volume":"39","author":"Sarnaik","year":"2021","journal-title":"J Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-005755","article-title":"Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts","volume":"10","author":"Chesney","year":"2022","journal-title":"J\u00a0ImmunoTherapy Cancer"},{"key":"B5","doi-asserted-by":"publisher","first-page":"JCO","DOI":"10.1200\/JCO-25-00765","article-title":"Long-term efficacy and safety of lifileucel tumor-infiltrating lymphocyte cell therapy in patients with advanced melanoma: A 5-year analysis of the C-144\u201301 study","author":"Medina","year":"2025","journal-title":"J Clin Oncol"},{"key":"B6","unstructured":"Package insert: AMTAGVI"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2025.43.16_suppl.9515","article-title":"Lifileucel in patients with advanced melanoma: 5-year outcomes of the C-144\u201301 study","volume":"43","author":"Medina","year":"2025","journal-title":"J Clin Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2025.43.16_suppl.9548","article-title":"Influence of tumor infiltrating\u00a0lymphocytes (TIL) monotherapy on persistent clinical and immunological responses in Asian metastatic melanoma patients with specific CD8+ TIL proportions: A phase I trial","volume":"43","author":"Cui","year":"2025","journal-title":"J Clin Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2025.43.16_suppl.e21508","article-title":"Safety, tolerance, and preliminary efficacy of autologous tumor-infiltrating lymphocytes (TILs) LM103 injection in Chinese patients with advanced melanoma and an exploration of the factors influencing the therapeutic effect","volume":"43","author":"Yang","year":"2025","journal-title":"J Clin Oncol"},{"key":"B10","unstructured":"LMBio. 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(BaseTIL-03M)"},{"key":"B55","unstructured":"Evaluation of a Pragmatic Approach to Adoptive Cell Therapy (ACT) Using an IL2 Analog (ANV419) vs High Dose IL2 After Tumor Infiltrating Lymphocytes (TIL) Therapy in Patients With Melanoma, NSCLC and Cervical Cancer (PragmaTIL) (PragmaTIL)"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1801722\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T06:55:56Z","timestamp":1774421756000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1801722\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,25]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2026.1801722"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1801722","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,25]]},"article-number":"1801722"}}