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Using patient-derived TIL-melanoma co-cultures, we identified and characterized a novel subset of CD8\n                  <jats:sup>+<\/jats:sup>\n                  TIL, capable of class I HLA-independent cancer cell lysis. The lymphotoxin \u03b2 receptor (LT\u03b2R) and interferon (IFN) sensing pathways were nominated as key determinants of TIL-mediated cancer cell killing from a whole-genome, loss-of-function CRISPR screen. Validation studies confirmed that dual LT\u03b2R and IFN sensing is necessary and sufficient for cancer cell lysis, and that expanded CD8\n                  <jats:sup>+<\/jats:sup>\n                  TIL express high lymphotoxin \u03b2 (\n                  <jats:italic>LTB<\/jats:italic>\n                  ) and upregulate lymphotoxin \u03b1 (\n                  <jats:italic>LTA<\/jats:italic>\n                  ) upon coculture with cancer cells. Leveraging paired scRNA-seq and scTCR-seq data, we confirmed that enrichment of\n                  <jats:italic>LTB<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  <jats:italic>CD8<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  T cells is associated with clinical response to TIL, and that\n                  <jats:italic>LTB<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  <jats:italic>CD8<\/jats:italic>\n                  <jats:sup>+<\/jats:sup>\n                  TIL are expanded from putative neoantigen-reactive,\n                  <jats:italic>LTB<\/jats:italic>\n                  <jats:sup>lo<\/jats:sup>\n                  CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells in resected tumors.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>We have uncovered a previously unrecognized mechanism of TIL-mediated tumor eradication, providing mechanistic insights into the role of LTBR\/IFN signaling in TIL-mediated cancer cell killing, and potentially offering insights into novel strategies to isolate, enrich, and expand tumoricidal TIL or augment specific TIL functions to enhance tumor control.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.19.689204","type":"posted-content","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T17:45:20Z","timestamp":1763574320000},"source":"Crossref","is-referenced-by-count":0,"title":["Lymphotoxin-driven cancer cell eradication by tumoricidal CD8\n                  <sup>+<\/sup>\n                  TIL"],"prefix":"10.64898","author":[{"given":"Hongyan","family":"Xie","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aiping","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aonkon","family":"Dey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph W.","family":"Dean","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan J.","family":"Perera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neal P.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex C. 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