Lymphotoxin-driven cancer cell eradication by tumoricidal CD8⁺ TIL.

ABSTRACT: Tumor-infiltrating lymphocyte (TIL) therapy is FDA-approved for patients with treatment-resistant advanced melanoma, but the TIL subpopulations critical for tumor eradication remains incompletely understood. Using patient-derived TIL-melanoma co-cultures, we identified and characterized a novel subset of CD8⁺ TIL, capable of class I HLA-independent cancer cell lysis. The lymphotoxin β receptor (LTβR) 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 LTβR and IFN sensing is necessary and sufficient for cancer cell lysis, and that expanded CD8⁺ TIL express high lymphotoxin β (LTB) and upregulate lymphotoxin α (L

SUBMITTER: Xie H 

PROVIDER: S-EPMC12667928 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature