{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T16:52:57Z","timestamp":1793465577363,"version":"4.5.0"},"reference-count":258,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"unspecified","delay-in-days":28,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,10,29]]},"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:p>Immunity to solid tumors is associated with the hallmarks of cancer-associated inflammation and the ability of immune mechanisms to limit tumor progression. Application of expanded tumor-infiltrating lymphocyte adoptive T cell therapy (TIL ACT) in clinical trials is now practiced at many sites around the world. Prior to immune checkpoint blockade (ICB), an approximate 50% objective response rate was consistently observed across multiple institutions for patients with melanoma. This now-approved strategy approaches 35% in recent studies from the USA and 49% with more highly selected patients in Europe. Here, we focus on early TIL studies in non-melanoma epithelial neoplasms. Increased understanding of cancer immunology has allowed changes in the TIL expansion process to include: (1) initial generation of TIL from fragments, (2) use of specialized large-scale culture vessels, (3) use of the rapid expansion protocol to enable \u2018young\u2019 TIL prosecution, and (4) treatment regimens employing non-myeloablative (NMA) chemotherapy followed by brief interleukin-2 administration. NMA leads to homeostatic proliferation of the transferred T cells, engraftment, profound neutropenia and lymphopenia, and improved clinical outcome. A key success of TIL ACT relies on the quality, specificity, and number of pre-existing TIL. This, in turn, is highly influenced by the suppressive tumor microenvironment. Thus, any means to alter \u2018cold tumor (non-T cell inflamed)\u2019 to \u2018hot tumor (T cell inflamed)\u2019 is theoretically desirable to improve both the quality and quantity of TIL obtained before harvest. Combinations of other immunotherapies such as application of ICB, co-stimulatory molecule agonist antibodies, autophagy inhibition, and dendritic cell support strategies could provide additional\u00ad improvements in TIL therapy and enable harnessing of the adaptive immune response to enhance the clinical outcome of TIL-ACT patients.<\/jats:p>","DOI":"10.1136\/jitc-2025-013420","type":"journal-article","created":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T04:55:20Z","timestamp":1764478520000},"page":"e013420","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["The science of tumor-infiltrating lymphocytes (TIL): perspectives from the SITC Surgery Committee"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct05468307","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05902520","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05902520","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03645928","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02858310","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06236425","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04072263","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05468307","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04052334","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03725605","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06566092","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06474676","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03935893","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05607095","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06566092","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06236425","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06783270","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8813-7367","authenticated-orcid":false,"given":"George","family":"Coukos","sequence":"first","affiliation":[{"name":"University Hospital of Lausanne, and Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4966-9752","authenticated-orcid":false,"given":"Marco","family":"Donia","sequence":"additional","affiliation":[{"name":"National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian R","family":"Gastman","sequence":"additional","affiliation":[{"name":"Iovance Biotherapeutics, San Carlos, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3317-9804","authenticated-orcid":false,"given":"Stephanie L","family":"Goff","sequence":"additional","affiliation":[{"name":"Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Gros","sequence":"additional","affiliation":[{"name":"Vall d\u2019Hebron Institute of Oncology (VHIO), Vall d\u2019Hebron Barcelona Hospital Campus, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Harari","sequence":"additional","affiliation":[{"name":"University Hospital of Lausanne, and Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Hernandez","sequence":"additional","affiliation":[{"name":"University of California San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6866-671X","authenticated-orcid":false,"given":"Fumito","family":"Ito","sequence":"additional","affiliation":[{"name":"University of Southern California, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay V","family":"Maker","sequence":"additional","affiliation":[{"name":"University of California San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9596-6785","authenticated-orcid":false,"given":"John E","family":"Mullinax","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranav","family":"Murthy","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6341-9971","authenticated-orcid":false,"given":"Sara I","family":"Pai","sequence":"additional","affiliation":[{"name":"Yale University School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangeetha","family":"Prabhakaran","sequence":"additional","affiliation":[{"name":"University of New Mexico, UNM Comprehensive Cancer Center, Albuquerque, New Mexico, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas P","family":"Restifo","sequence":"additional","affiliation":[{"name":"Medici Therapeutics, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie L","family":"Silver","sequence":"additional","affiliation":[{"name":"Cleveland Clinic, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Marincola Smith","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Turcotte","sequence":"additional","affiliation":[{"name":"Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al, Montreal, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick L","family":"Wagner","sequence":"additional","affiliation":[{"name":"Allegheny Health Network Cancer Institute, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8935-5008","authenticated-orcid":false,"given":"James C","family":"Yang","sequence":"additional","affiliation":[{"name":"Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3988-5419","authenticated-orcid":false,"given":"Michael T","family":"Lotze","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,11,29]]},"reference":[{"key":"2026091123003630000_13.11.e013420.1","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1016\/j.annonc.2025.06.005","article-title":"Health-related quality of life of patients with metastatic melanoma treated with tumor-infiltrating lymphocytes compared with ipilimumab in a randomized phase III trial","volume":"36","author":"Ten Ham","year":"2025","journal-title":"Ann Oncol"},{"key":"2026091123003630000_13.11.e013420.2","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2020-001583","article-title":"Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee","volume":"8","author":"Gastman","year":"2020","journal-title":"J Immunother Cancer"},{"key":"2026091123003630000_13.11.e013420.3","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2024-010207","article-title":"Art of TIL immunotherapy: SITC\u2019s perspective on demystifying a complex treatment","volume":"13","author":"Turcotte","year":"2025","journal-title":"J Immunother Cancer"},{"key":"2026091123003630000_13.11.e013420.4","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz398"},{"key":"2026091123003630000_13.11.e013420.5","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.annonc.2024.07.723","article-title":"Efficacy of TIL therapy in advanced cutaneous melanoma in the current immuno-oncology era: updated systematic review and meta-analysis","volume":"35","author":"Mart\u00edn-Lluesma","year":"2024","journal-title":"Ann Oncol"},{"key":"2026091123003630000_13.11.e013420.6","doi-asserted-by":"crossref","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 of the C-144-01 study","volume":"10","author":"Chesney","year":"2022","journal-title":"J Immunother Cancer"},{"key":"2026091123003630000_13.11.e013420.7","doi-asserted-by":"crossref","unstructured":"Medina T , Chesney JA , Kluger HM , et al . Long-term Efficacy and Safety of Lifileucel Tumor-infiltrating Lymphocyte (TIL) Cell Therapy in Patients with Advanced Melanoma: A 5-year Analysis of the C-144-01 Study. 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