{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:18Z","timestamp":1792787298356,"version":"4.5.0"},"reference-count":35,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"unspecified","delay-in-days":20,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["32300757"],"award-info":[{"award-number":["32300757"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Shenzhen Medical Research Fund","award":["A2303022"],"award-info":[{"award-number":["A2303022"]}]},{"name":"Shenzhen Science and Technology Program","award":["JCYJ20240813150415021"],"award-info":[{"award-number":["JCYJ20240813150415021"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["2023A1515220239 and 2024A1515010598"],"award-info":[{"award-number":["2023A1515220239 and 2024A1515010598"]}]},{"name":"100 Top Talents Program of Sun Yat-sen University and Research Start-up Fund of the Seventh Affiliated Hospital, Sun Yat-sen University","award":["ZSQYBRJH0027"],"award-info":[{"award-number":["ZSQYBRJH0027"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,8,30]]},"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The immunosuppressive tumor microenvironment in hepatocellular carcinoma (HCC) limits the efficacy of current immunotherapies. The interplay between the emerging inhibitory receptor NKG2A and its activating counterpart NKG2C, both binding HLA-E, and its interaction with the PD-1-PD-L1 pathway in cancer remains unclear. This study aims to delineate the functional network formed by these pathways in shaping the immunosuppressive landscape of HCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed public databases and performed immunohistochemistry on HCC tissues to assess HLA-E expression and prognostic relevance. Tumor-infiltrating lymphocytes from patient samples were examined by flow cytometry to evaluate the functional impact of NKG2A, NKG2C, and PD-1 expression on T and NK cells. Single-cell RNA and T cell receptor (TCR) sequencing were employed to characterize immune subset heterogeneity. Functional assays and mouse models were used to evaluate the effects of NKG2A and PD-1 blockade.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In the absence of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell infiltration, elevated HLA-E expression in HCC tissue correlated with poorer overall survival in non-immunotherapy-treated patients. Conversely, in the presence of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, high HLA-E expression was linked to an inflammatory tumor microenvironment characterized by IFN-\u03b3-producing T cells, and increased major histocompatibility complex I, which was associated with improved patient response to immunotherapy. Tumor-infiltrating CD8\n                      <jats:sup>+<\/jats:sup>\n                      T and NK cells from HCC patients upregulated NKG2A, conferring tissue-resident memory and tumor-reactive characteristics while simultaneously impairing cytotoxic function. Single-cell RNA and TCR sequencing revealed differential expression patterns of NKG2A, NKG2C, and PD-1 in different T and NK cell subsets, with NKG2A\n                      <jats:sup>+<\/jats:sup>\n                      PD-1\n                      <jats:sup>+<\/jats:sup>\n                      T cells relevant to antigen-specific clonal expansion. Mechanistically, the inhibitory effect mediated by the NKG2A-HLA-E axis contributed more prominently than the stimulatory role of the NKG2C-HLA-E axis in suppressing antitumor immunity. Furthermore, the NKG2A-HLA-E axis acted cooperatively with the PD-1-PD-L1 axis to promote CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell dysfunction. Combined blockade of NKG2A and PD-1 enhanced the cytotoxic activity of tumor-infiltrating CD8\n                      <jats:sup>+<\/jats:sup>\n                      T and NK cells, resulting in potent tumor eradication in vitro and in vivo, outperforming single-agent treatments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings identify the NKG2A-HLA-E axis as an important immunoregulatory pathway associated with immune suppression in HCC and provide a rationale for further evaluation of combined NKG2A and PD-1 blockade strategies.<\/jats:p>\n                  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