biostudies-literatureZakeri NCancer Research UKNational Institute for Health Research (NIHR)Wellcome Trust1372https://www.ebi.ac.uk/biostudies/studies/S-EPMC8927126biostudies-literatureUnknown13(1)Immunotherapy is now the standard of care for advanced hepatocellular carcinoma (HCC), yet many patients fail to respond. A major unmet goal is the boosting of T-cells with both strong HCC reactivity and the protective advantages of tissue-resident memory T-cells (T_RM). Here, we show that higher intratumoural frequencies of γδ T-cells, which have potential for HLA-unrestricted tumour reactivity, associate with enhanced HCC patient survival. We demonstrate that γδ T-cells exhibit bona fide tissue-residency in human liver and HCC, with γδT_RM showing no egress from hepatic vasculature, persistence for >10 years and superior anti-tumour cytokine production. The Vγ9Vδ2 T-cell subset is selectively depleted in HCC but can efficiently target HCC cell lines sensitised to accuNature communicationsCharacterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma.PMC8927126214191/Z/18/Z21419117547926603Pinzani MZakeri NDavidson BRKucykowicz SQuaglia AAmin OEGander AMaini MKSwadling LSchmidt NMPallett LJDiniz MOHall AfalseCharacterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma.Immunotherapy is now the standard of care for advanced hepatocellular carcinoma (HCC), yet many patients fail to respond. A major unmet goal is the boosting of T-cells with both strong HCC reactivity and the protective advantages of tissue-resident memory T-cells (T_RM). Here, we show that higher intratumoural frequencies of γδ T-cells, which have potential for HLA-unrestricted tumour reactivity, associate with enhanced HCC patient survival. We demonstrate that γδ T-cells exhibit bona fide tissue-residency in human liver and HCC, with γδT_RM showing no egress from hepatic vasculature, persistence for >10 years and superior anti-tumour cytokine production. The Vγ9Vδ2 T-cell subset is selectively depleted in HCC but can efficiently target HCC cell lines sensitised to accu2022-01-01T00:00:00Z2022 Mar2025-04-19T22:10:37.133Z2025-04-19T22:10:37.133ZS-EPMC89271263529665810.1038/s41467-022-29012-1